Deformation of cholesteric elastomers by uniaxial stress along the helix axis.

The deformation of cholesteric elastomers by mechanical stress applied parallel to the helix axis is studied by calculation of the free-energy density. The Frank-elasticity contribution is taken into account. A chiral solvent, present at cross-linking time, is in general considered to be replaced after cross-linking by a solvent with different chirality. Two special cases considered are zero and unchanged solvent chirality, the first known as that of imprinted cholesteric elastomers, the latter equivalent to intrinsic cholesteric elastomers with chemically attached chiral groups. Depending on material parameters and imposed strain, the director can show a tilt towards the helix axis up to the maximum tilt, corresponding to a nematic state. In case of intrinsic elastomers with low conformation anisotropy, direct transitions from untilted to nematic states can be induced by straining. The helix structure of the director field is coarsened with an average wave number different to that of the information inscribed in the network at cross-linking time, if this lowers the average free-energy density. Switching between different states can be achieved with electric fields of reasonable values applied parallel to the helix axis. Spectra of the reflection of polarized light are calculated.

The efficacy and safety of zidovudine alone or as cotherapy with acyclovir for the treatment of patients with AIDS and AIDS-related complex: a double-blind randomized trial. European-Australian Collaborative Group.

OBJECTIVE: To evaluate the efficacy and safety of zidovudine (ZDV) at a maintenance dose of 250 mg every 6 h alone or as cotherapy with acyclovir (ACV; 800 mg every 6 h) as treatment for AIDS and AIDS-related complex (ARC). DESIGN: Double-blind, randomized, placebo-controlled clinical trial of up to 1 year's therapy. SETTING: Teaching hospital ambulatory clinics in eight European countries and Australia. SUBJECTS: A total of 131 patients with AIDS and 134 with ARC were enrolled and followed from 1986 to 1988. MAIN OUTCOME MEASURES: Time to development of AIDS-defining opportunistic infections and AIDS-associated neoplasms, survival assessed at 1 year after entry, performance status, body weight, CD4+ cell counts. RESULTS: During the study period, 46 (36%) ZDV recipients and 37 (27%) cotherapy recipients developed opportunistic infections. The probability of an ARC patient progressing to AIDS (1982 Centers for Disease Control criteria) was 0.18 and 0.15 [95% confidence interval (CI) for difference, -0.17 to 0.11] for the ZDV alone and cotherapy recipients, respectively. After excluding patients who experienced an opportunistic infection during the first 4 weeks of therapy, the probability was 0.13 and 0.099 (95% CI for difference, -0.16 to 0.10) for the ZDV and cotherapy recipients, respectively. Thirty-six patients treated with single-agent therapy [28 (41%) AIDS and eight (12%) ARC patients] and 15 cotherapy recipients [13 (21%) AIDS and two (3%) ARC patients] died during the study. There was a significant difference in time to death between the cotherapy and ZDV alone groups for both AIDS (P = 0.014) and ARC (P = 0.045) patients, with cotherapy patients surviving longer. Infections related to herpesviruses, but not cytomegalovirus, were reduced in patients receiving ACV therapy. CD4+ cell counts in both arms generally increased initially and then declined. Forty-six per cent of patients in the ZDV group (59% of AIDS and 31% of ARC patients) and 52% of patients in the cotherapy group (69% of AIDS and 34% of ARC patients) experienced bone-marrow suppression. Red cell transfusions were administered to 33% of ZDV alone recipients and 34% of cotherapy recipients. CONCLUSION: These data show that the addition of high-dose ACV cotherapy to ZDV for patients with AIDS and advanced ARC results in a statistically significant improvement in survival with minimal increase in the risk of toxicity.

Bactericidal activity of ofloxacin versus roxithromycin in the treatment of Streptococcus pneumoniae.

Ofloxacin is highly active against Gram-negative aerobic bacilli, but moderately active against Gram-positive cocci. The minimal inhibitory concentrations (MICs) against Streptococcus pneumoniae range between 1 and 2 mg/L. MICs of roxithromycin (RU 28965) against S. pneumoniae range between 0.004 and 0.03 mg/L, but Gram-negative bacilli are resistant. The bactericidal activities of ofloxacin and roxithromycin were evaluated against 15 strains of S. pneumoniae, which were isolated recently from clinical specimens. Killing activity was evaluated under conditions simulating serum pharmacokinetic parameters. Initial concentrations were 10 mg/L for roxithromycin and 2 mg/L for ofloxacin, and the half-life was 6 hours for both compounds. Under these conditions, roxithromycin was rapidly bactericidal. The speed at which pneumococci were killed was faster with roxithromycin than with ofloxacin. No regrowth was seen with roxithromycin, but regrowth occurred in 8 of 15 strains with ofloxacin.

Interaction between quinolones and caffeine.

The effects of multiple doses of ofloxacin 200 mg, ciprofloxacin 250 mg or enoxacin 400 mg (all twice daily) on the pharmacokinetic properties of single doses of caffeine (220 to 230 mg) were investigated in 12 healthy volunteers. Intraindividual comparisons showed that ciprofloxacin and enoxacin significantly inhibited the elimination of caffeine. Ofloxacin, however, did not affect any of the measured pharmacokinetic properties of caffeine. Thus, caffeine should be avoided in patients with liver disorders, cardiac arrhythmias, latent epilepsy or in intensive care while undergoing treatment with enoxacin or ciprofloxacin.

Cefotaxime versus ceftriaxone for the treatment of nosocomial pneumonia. Results of a multicenter study.

Third-generation cephalosporins are the drugs of choice for serious nosocomial pneumonia; however, the recommended dosages are controversial. Our study compared two of these cephalosporins and showed that 2 g cefotaxime every 12 h and 4 g ceftriaxone once daily or 2 g every 12 h proved to be effective therapies for these chest indications.

In vitro activity of lomefloxacin (NY-198 or SC 47111).

The activity of lomefloxacin was compared to that of four other quinolones. Minimum inhibitory concentrations (MICs) were similar to those of enoxacin, norfloxacin, and ofloxacin against the Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus spp. and Enterococcus faecalis. The activity of lomefloxacin was antagonized in urine at pH 5.4, but not in urine at pH 7.0. Higher inocula required higher lomefloxacin concentrations for inhibition. Lomefloxacin was more active at alkaline pH. At concentrations equal to or 2-fold the MIC, it was rapidly bactericidal against Gram-negative organisms and required a longer time for the reduction of inoculum by 99% and 99.9%. An "Eagle effect" was seen against Escherichia coli and Staphylococcus aureus but not against P. aeruginosa.

Prospective randomized study to compare imipenem 1.5 grams per day vs. 3.0 grams per day in infections of granulocytopenic patients.

The objective of this presented prospective randomized study was to compare the efficacy of empirical antimicrobial monotherapy with imipenem 3 x 0.5 g per day to 3 x 1.0 g per day for treatment of infections in neutropenic patients. A total of 192/220 febrile episodes were evaluable for clinical efficacy. The overall response rate was 53/93 (57%) vs. 57/99 (58%). Of the different infection types, fever of unknown origin (FUO) showed the best response, with defervescence in 29/41 (71%) and 36/42 (86%) cases, respectively (not significant). Unfavourable results were found in pneumonias [5/20 (25%) vs. 4/23 (17%)]. The median time until persistent defervescence was equal in both groups (2 days), likewise the median duration of imipenem therapy in responders (7 days). The most frequent micro-organisms were Gram-negative, documented in 22% of the febrile episodes in the lower dosage group vs. 17% of all episodes in the patients with imipenem 3.0 g per day (Gram-positives 17% vs. 14%, fungal 5% vs. 8%). In the lower dosage group, fever with abdominal symptoms occurred less frequently (8% vs. 15%), and significantly more patients tolerated imipenem without any side-effects (95.8% vs. 79.4%), especially regarding severe nausea/vomiting (2.1% vs. 11.8%). Of the initial non-responders, 35/40 (88%) vs. 41/42 (98%) were cured after therapy modification. There was no significant difference in the use of further antibiotics such as aminoglycosides, glycopeptides, ceftazidime or amphotericin B, except a marginally higher use of metronidazole in patients with imipenem 3.0 g per day (3% vs. 10%). Overall, we found no significant differences in efficacy between the two study groups, but more frequent side-effects with imipenem 3.0 g per day.

In vitro activity of HR 756, a new cephalosporin compound.

The in vitro activity of HR 756, a new cephalosporin, has been determined against recent clinical isolates and compared with that of other beta-lactam antibiotics. The geometric means of the minimum inhibitory concentrations (MIC) for different isolates of Escherichia coli (100 isolates), Klebsiella pneumoniae (84), Pseudomonas aeruginosa (121), Proteus mirabilis (52), indole-positive Proteus species (9), Salmonella species (19), Staphylococcus aureus penicillin-sensitive (29) and penicillin-resistant (39) were: 0.095, 0.124, 11.1, 0.095, 0.0107, 0.078, 1 and 0.95 mcg/ml, respectively. Its activity was affected by rise in inoculum against S. aureus and P. aeruginosa but not against K. pneumoniae and E. coli. Bactericidal activity was determined by membrane filtration method. HR 756 was found to be bactericidal to E. coli, K. pneumoniae, P. aeruginosa and Proteus species. Although the MICs of the tested S. aureus strains were 1 mcg/ml, 5 mcg/ml of HR 756 failed to kill 99% of the inoculum within 24 hours.

Incidence of myocardial infarctions in HIV-infected patients between 1983 and 1998: the Frankfurt HIV-cohort study.

OBJECTIVE: To investigate whether the use of highly active antiretroviral therapy (HAART) is associated with an increased incidence of myocardial infarctions (MI) in HIV infected patients. DESIGN: Retrospective analysis of a cohort of 4993 HIV infected patients treated at our hospital between January, 1 1983 and December, 31 1998. The incidence of myocardial infarctions during 4 observation periods with different antiretroviral treatment strategies are compared. Possible risk factors for MI are evaluated by univariate analysis and using a multiple regression model. RESULTS: 29 patients with MI were diagnosed between 1983 and 1998. The incidence of MI per 1000 patient-years increased from 0.86 (1983-86), 1.14 (1987-90), 0.59 (1991-94) to 3.41 (1995-98) respectively (p = 0.002). Age >40, previous HAART therapy, homo-, or bisexual mode of HIV transmission and previous AIDS diagnosis were significantly associated with MI in univariate analysis. Age >40 and previous HAART therapy remained significantly associated with MI in a multiple regression model. CONCLUSION: The incidence of MI in HIV infected patients increased in our cohort after the introduction of HAART.

Control of intracellular growth of Mycobacterium fortuitum by human monocytes in vitro.

The ability of human monocytes to phagocytize and respond to infection by Mycobacterium fortuitum was tested using the method of Crowle and May. The monocytes were obtained from heparinized donor blood samples and separated from lymphocytes by adherence to plastic surfaces. M. fortuitum infection was performed immediately. Intracellular viability was indicated by colony forming units (CFU) done at 2 hour intervals. Monocytes were found to cause a rapid reduction in CFU during the first 2 hours of incubation. The rate of killing of M. fortuitum decreased thereafter but continued for the entire 8-hour study period. In parallel tests, ciprofloxacin and ofloxacin were added to the culture medium. Increased intracellular killing was observed with drug concentrations above 2 x MIC in both cases. Ofloxacin showed better antimycobacterial effects than ciprofloxacin.

Piperacillin/tazobactam versus cefepime as initial empirical antimicrobial therapy in febrile neutropenic patients: a prospective randomized pilot study.

The objective of the presented prospective, randomized study was to compare the efficacy of empirical antimicrobial monotherapy with piperacillin/tazobactam (PIP/TAZ) to cefepime (CEFP) for treatment of infections in neutropenic patients. From a total of 102 febrile episodes 100 were evaluable. The most frequent microorganisms were gram-negative, documented in 22% vs. 24% of the febrile episodes (gram-positives 18% vs. 16%, fungi 2% vs. 4%). The response rate was similar with 22/51 (43%) of episodes treated with PIP/TAZ vs. 19/49 (39%) with CEFP. Of the different infection types classified at the end of the febrile episodes, patients with fever of unknown origin (FUO) and primary bacteremias showed the best initial responses with 25/44 (57%) and 11/22 (50%). Lower initial response rates were found in pneumonias with totally 3/13 (23%) and other clinically documented infections with 2/21 (10%), without any difference between both groups. Gram positive infections showed a higher response with PIP/TAZ than with CEFP (4/9 vs. 0/8), gram negative responded less frequently (3/11 vs. 7/13). The median time until persistent defervescence was equal in both groups (2.5 vs. 2 days), likewise the response rates after the different steps of therapy modifications (change to imipenem or ceftazidim, or addition of gentamycin, vancomycin or amphotericin B). Totally, 96% of febrile episodes responded in both therapy arms. Overall, we found no significant differences in efficacy between the two therapeutic regimens. In conclusion, PIP/TAZ as well as CEFP might be a sufficient initial therapy for febrile neutropenia, but further randomized trials with larger patient numbers are necessary.

Bactericidal activity of tigemonam, alone and in combination with gentamicin.

The in vitro bactericidal activity of tigemonam, alone and in combination with gentamicin, was evaluated against various strains of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Salmonella enteritidis, Enterobacter cloacae, Proteus mirabilis, and Proteus vulgaris. Minimum inhibitory and bactericidal concentrations were determined on three consecutive days with an inoculum of 10(5) colony-forming units (CFU)/mL or a culture in the logarithmic growth phase. The results found tigemonam to be rapidly bactericidal against most Enterobacteriaceae isolated. In addition, the killing curves indicated a synergism between tigemonam and subinhibitory concentrations of gentamicin.

Experience with imipenem in internal medicine--a postmarketing surveillance study.

Imipenem was registered for clinical use in Germany in 1985. It is recommended for initial treatment in either severe nosocomial infections or infections in ICU or immunocompromised patients. In this study, we evaluated 1,215 patients who were prescribed imipenem at our Zentrum der Inneren Medizin-a major tertiary care university hospital-over a 6 year period. 650 of 1,215 patients (53.5%) had rapidly fatal disease; and the main indication for imipenem was pneumonia and fever of unknown origin. 56.2% received 500 mg imipenem t.i.d., 40.4% 500 mg b.i.d., 0.9% 1000 mg b.i.d.; and 2.5% 1000 mg t.i.d. Average duration of treatment was 11 days. Lower dose (500 mg b.i.d.) was used in patients with renal insufficiency; highest dose was used in severe infections or infections caused by moderately sensitive organisms. Imipenem was used as a single initial antibacterial agent in the majority of the patients. Success was seen in 80% of the episodes, irrespective of the dosage used; 89% at 500 mg b.i.d., 74% at 500 mg t.i.d., 77% at 1,000 mg b.i.d.; and 69% at 1,000 mg t.i.d. We observed the highest favourable response (91.5%) in the episodes treated initially with imipenem monotherapy. Overall, imipenem was well tolerated. The majority of the patients with untoward effects was on multiple-drug regimens. The most frequent untoward event observed involved the gastrointestinal tract.

Uptake and killing of Candida by human peritoneal macrophages and amphotericin B.

The effects of amphotericin B at subinhibitory and inhibitory concentrations on ingestion and intracellular killing of C. albicans ATCC 10,231 and C. tropicalis ATCC 13,803 by human peritoneal macrophages in vitro was investigated. Peritoneal macrophages were harvested from overnight peritoneal dialysate of 26 patients undergoing regular continuous ambulatory peritoneal dialysis (CAPD) using a new simple isolation technique. Macrophages were suspended with Candida (1:2-3) together with pooled human serum and with or without amphotericin B at various concentrations. Vital staining with acridine orange at a very low concentration using the metachromatic property of the dye allowed simultaneous assessment of ingestion and intracellular viability of the yeasts. Counts of Candida in 100 macrophages were performed at 1, 2, 3, 4, 6 and 24 h under a fluorescence microscope at 1000x and the ratios of living to dead intracellular Candida were calculated. Amphotericin B was added at concentrations of 0.1, 1 and 10 times the MIC. Ingestion was rapid and complete, while intracellular killing ranged from 4-69% for C. albicans and from 9-48% for C. tropicalis. Amphotericin B at 1 MIC enhanced the killing of C. tropicalis (factor 1.32) but reduced killing of C. albicans (factor 0.6) after 6 h.

In vitro activity of norfloxacin in synthetic media and human urine compared to that of cinnoxacin, nalidixic acid and pipemidic acid.

Activity of norfloxacin was compared to that of cinnoxacin, nalidixic acid and pipemidi acid in DST-agar and human urine solidified by adding 1.2% agar. Norfloxacin was the most active compound when tested on DST-agar but the MIC values increased from 64 to 128 fold when tested in urine. Other compounds also showed an increase in MIC in urine-agar, but the increase was less marked. MICs for norfloxacin in DST-agar and Müller-Hinton-Agar were similar. Higher concentrations were required in Müller-Hinton-Broth than in Müller-Hinton-Agar.

Hazard detection by illness pattern similarities.

Health hazard detection was investigated by using cluster analysis of illness patterns of occupational groups. This approach was expected to avoid the bias problems of simple illness rates and to detect hazards by their effects on illness severity. The practical use of this approach lead to the following criterion: an environmental exposure of people associated with an illness pattern typical of a more advanced age is a health hazard. The use of this criterion and methodology is widely applicable in industry and the prospect for further improvement in detection methods is good.

Hepatitis A epidemics from utility sewage in Ocoee, Florida.

The 1988-1989 hepatitis A epidemic in the Palms section of Ocoee, Florida, followed sewage overflows and involved 39 cases and a fetal death. Of the 18 index cases (i.e., the first hepatitis illness in a household), each had a history of contact with sewage-contaminated stormwater and no other known contact with the infection. Illnesses varied from mild to severe; 20 people reported that diarrhea, abdominal pain, varying degrees of ascites, and other symptoms continued for 2 y after the initial illness. Health injuries up to 20 y of lost life, measured by CEA-Clinical Epidemiological AnalysisSM, were found. Public records of rainfall and sewage flows provide evidence of massive stormwater entry into the utility system, which periodically appears to have flushed sewage from the utility lift station into residential areas.

[Comparison of the effect of 2 therapy concepts in the treatment of Pneumocystis carinii pneumonia. Cotrimoxazole for 21 days versus sequential therapy with cotrimoxazole followed by pentamidine inhalation]. / Wirkungsvergleich zweier Therapiekonzepte zur Behandlung der Pneumocystis-carinii-Pneumonie. Cotrimoxazol für 21 Tage versus Sequenztherapie mit Cotrimoxazol und anschliessender Pentamidin-Inhalation.

Standard therapy of pneumocystis carinii pneumonia with cotrimoxazole and intravenous pentamidine second line therapy both have a response rate of 75 to 90%. As severe side effects, myelotoxicity and skin reaction have been observed which may occur from treatment day 7 on. In order to prevent such side effects as well as reduce hospitalization times, an open, randomized pilot study was designed. Object of this study was the comparison of efficacy and safety of two different treatment schemes: standard therapy versus sequential treatment. Twelve patients were treated according to study design: five patients with cotrimoxazole only, and seven patients with sequential therapy consisting of cotrimoxazole followed by pentamidine aerosol. All patients were treated for 21 days. Four out of five patients with cotrimoxazole, and two out of seven patients with sequential therapy, were successfully treated and had no pneumocystis carinii pneumonia relapses within four weeks after termination of treatment. Each group had one treatment failure. Four patients under sequential treatment were not evaluable. - In spite of the rather unfavourable preliminary results, the study should be continued. However, patients with secondary opportunistic infections respectively other severe diseases should not be included into the study.

[Clinical use of new cephalosporins for severe infections in internal medicine]. / Klinischer Einsatz neuer Cephalosporine bei schweren Infektionen in der inneren Medizin.

Our clinical experience with new antibiotics giving special consideration to the individual cephalosporin groups is discussed. Although newer cephalosporins from cefamandol and cefoxitin to cefotiam and cefoperazon already showed increased effectiveness (for example, cefoxitin in bacteroides infection) in comparison to older ones, the real breakthrough regarding enterobacteriaceae was only made with cephalosporins of the cefotaxime group. This group's main indication is non-specific initial therapy of severe nosocomial infections, especially processes in which the presence of resistant enterobacteriaceae must be assumed. Because of its broad spectrum of action, cefotaxime can to a large extent replace the combinations with aminoglycosides which were used previously. When required, cefotaxime proves to be a good partner for combinations with pseudomonas antibiotics.

[Atherosclerosis--a chronic infectious disease caused by Chlamydia pneumoniae]. / Arteriosklerose--eine chronische Infektionskrankheit durch Chlamydia pneumoniae.

Recent investigations allow a controversial but convincing interpretation of the pathogenesis of atherosclerosis (arteriosclerosis). Atherosclerosis can be apparently the result of ultrachronic persistent infection by Chlamydia pneumoniae and not the result of heterogenous risk factors. The main arguments for the chlamydial genesis are: Correlation of coronary heart disease and other atherosclerotic diseases and antibodies against Chlamydia pneumoniae. Chlamydia pneumoniae could be detected with different techniques (PCR, ICC, immunohistology, electromicroscopy, culture) in a high percentage in atheromas from different sites. Three successful international studies with macrolides in coronary heart disease. Target cells of atherosclerosis (endothelia, macrophages, muscle cells) can be infected by Chlamydia pneumoniae in vitro. Provocation of an arteriitis in animal experiments. The reduction of incidence of atherosclerotic diseases since the 1960s, probably due to advanced antibiotic therapy. Elevated acute-phase proteins and other inflammatory signs (CRP, WBC count, fibrinogen) briefly before occurrence of myocardial infarction. There are good arguments for intervention studies in coronary heart disease and other manifestations of atherosclerosis. The relevant antibiotics are licensed for chlamydial infections, cheap and safe. Meticulous records and long-term observation of patients need to be developed, sometimes contrary to interests of the pharmaceutical industry.