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Background In a context of the evolution of severe morbidities in patients living with HIV (PLWH), the aim of this study was to describe reasons for hospitalization and the mode of care for the patients requiring hospitalization. Methods All admissions (≥ 24 h) of PLWH to 10 hospitals in the south of Paris (COREVIH Ile-de-France Sud) between 1/1/2011 and 12/31/2011 were identified. The hospital database and the file of patients followed in the HIV referral department of each hospital were matched. Detailed clinical and biological data were collected, by returning to the individual medical records, for a random sample (65% of hospitalized patients). Results A total of 3013 hospitalizations (1489 patients) were recorded in 2011. The estimated rate of hospitalized patients was about 8% among the 10105 PLWH routinely managed in COREVIH Ile-de-France Sud in 2011. The majority (58.5%) of these hospitalizations occurred in a unit other than the HIV referral unit. Non-AIDS-defining infections were the main reason for admission (16.4%), followed by HIV-related diseases (15.6%), hepatic/gastrointestinal diseases (12.0%), and cardiovascular diseases (10.3%). The median length of stay was 5 days overall (IQR: 2-11), it was longer among patients admitted to a referral HIV care unit than to another ward. HIV infection had been diagnosed > 10 years previously in 61.4% of these hospitalized patients. They often had associated comorbidities (coinfection HCV/HVB 40.5%, smoking 45.8%; hypertension 33.4%, dyslipidemia 28.8%, diabetes 14.8%). Subjects over 60 years old accounted for 15% of hospitalized patients, most of them were virologically controlled under HIV treatment, and cardiovascular diseases were their leading reason for admission. Conclusion Needs for hospitalization among PLWH remain important, with a wide variety in causes of admission, involving all hospital departments. It is essential to prevent comorbidities to reduce these hospitalizations, and to maintain a link between the management of PLWH, that becomes rightly, increasing ambulatory, and recourse to specialized inpatient services.

The article summarizes current trends in the use of umbilical cord blood components in medical practice and describes the origin, types and tendencies of cord blood banks development in Ukraine and abroad. Presented results of the opinion poll of residents of different regions of Ukraine on the subject “stem cells” / “cell therapy” demonstrate a high awareness and interest of various sociological categories of the population on modern medical technologies using stem cells as well as positive attitude of pregnant women and obstetricians towards cord blood banking. The importance of creating a public cord blood bank in Ukraine is substantiated.

An increased inflammatory mass in the subarachnoid space during bacterial meningitis may correlate with a poor outcome of disease. Using a rabbit model of pneumococcal meningitis, we sought to reduce this inflammatory process. The ability of the pneumococcal cell wall to cause death and to generate leukocytosis and abnormal chemistry in cerebrospinal fluid was prevented when animals were treated with inhibitors of the cyclooxygenase pathway of arachidonate metabolism. Bacterial lysis by ampicillin led to release of cell wall that caused a significant, transient increase in meningeal inflammation. This inflammatory burst was also prevented by administering cyclooxygenase inhib-itors concurrently with the antibiotic

Pneumococcal cell wall induces meningeal inflammation in rabbits injected intracisternally with greater than 10(5) cell equivalents. Both of the major cell wall components, teichoic acid and peptidoglycan, contribute to this inflammatory activity although responses differ depending on the chemical nature, size, and complexity of these fractions. Challenge with teichoic acid (membrane or wall associated) results in greater inflammation at 5 hr than at 24 hr. Degraded teichoic acid is inactive. In contrast, the inflammation caused by whole cell wall or high-molecular-weight peptidoglycan-containing fractions increases in intensity from 5 to 24 hr. Peptidoglycan fractions lose activity at 24 hr when hydrolyzed to disaccharide-stem peptide moieties. Generation of free cell wall components in cerebrospinal fluid as, for example, during treatment with antibiotics that are bacteriolytic as well as bactericidal, could contribute to increased inflammation in the subarachnoid space.

A pneumococcal isolate that caused relapsing meningitis in a patient infected with human immunodeficiency virus (HIV) was found to display an unusual response to penicillin--rapid death but a striking lack of cellular lysis. This lytic defect was also detected in all four pneumococcal isolates from three additional HIV-infected patients and in more than half of the clinical isolates from patients with bacteremia. In a rabbit model of meningitis, the lysis-defective strain remained cryptic, with a delay of 5 h in the onset of leukocytosis in cerebrospinal fluid. A marked burst of leukocytosis was associated with ampicillin-induced lysis of a lysis-sensitive strain but not of a lysis-defective strain. Pneumococcal clinical isolates have different lytic responses to penicillin; defective lysis may adversely affect the course of meningitis, an observation suggesting that autolysins play a role in modulating infectious diseases.

Summary Experiments to evaluate the effect of the level and duration of endotoxaemia on the meningeal inflammatory response were performed in order to determine if systemic inflammation alters meningitis. Rabbits received either saline or Escherichia coli O111:B4 lipopolysacharide (LPS) intravenously at various doses (1, 3 or 10 µg) and times (−8, −2 or 0 h) before an intracisternal injection of 20 ng LPS. An intracisternal LPS injection together with saline intravenously produced a peak cerebrospinal fluid (CSF) tumour necrosis factor (TNF) level (95 ± 26 ng/ml) at 2 h and peak leucocyte level (5413 ± 764 cells/µl) at 4 h post-injection. Blood leucocytes were slightly elevated (12 000 ± 500/µl at 0 h; 16 900 ± 280/µl at 8 h) but plasma TNF was always undetectable ( 8 ng/ml), but plasma TNF was always detectable (> 0·2 ng/ml at 10 h post-intravenous dose). Intravenous LPS administration at 0 h also blocked pleocytosis, but the inhibitory effect was lost when administration at −8 h. In conclusion, the degree and duration of endotoxaemia affect the meningeal inflammatory response to LPS in experimental meningitis.

The postantibiotic effect (PAE) is the persistent inhibition of bacterial growth after a brief exposure to an antibiotic. Most beta-lactams do not induce a PAE for Gram-negative bacteria, but PAEs have been reported for carbapenems and penems. This study investigated the effect of sequential doses of imipenem on the PAE for Pseudomonas aeruginosa and Escherichia coli cultures in a chemostat. The PAE for the bacterial population did not change even after six successive exposures to imipenem. Nevertheless, screening of colonies isolated after repeated drug exposure identified a single P. aeruginosa mutant whose imipenem PAE was shortened, although the MIC was unchanged. The PAEs for the parent and mutant were studied in vitro in batch culture by monitoring: (i) viable counts; (ii) electrical impedance of the culture medium; (iii) incorporation of radiolabelled N-acetyl-D-glucosamine and (iv) cell volume changes. PAEs for the parent and mutant were found to be significantly different by all in-vitro methods used. Moreover, the median cell volume in antibiotic-exposed cultures remained much smaller and less heterogeneous than in the control cultures, even though both cultures were growing at the same rate. The mutant was found to have a reduced expression of a 52 kDa outer membrane protein. These observations suggest that factors in addition to suppression of bacterial growth should be considered when studying the PAE. The PAEs of imipenem for the parent and mutant were studied in a thigh infection model in leucopenic mice. Similar PAEs were observed in vivo for both parent and mutant in one experiment and no PAEs for either organism were found in a second experiment. This study showed that although the PAE is a stable in-vitro phenomenon, the lack of correlation between the in-vitro and in-vivo results warrants caution in attributing clinical significance to the PAE of imipenem.

For clinical trials of anti-infective drugs for the treatment of vascular access device-related bloodstream infections, patients should be identified and enrolled on the basis of current standards for the clinical diagnosis of such infections. To ensure comparability of patients, only those infected with staphylococci and Candida species should be included. A prospective, randomized, double-blind design is recommended. Future protocols may include abbreviated courses of therapy, treatment with combinations of drugs, or a progression from parenteral to oral therapy. Clinical response is judged as cure, failure, or indeterminate response; there is no "improved" category. Microbiological response is categorized as eradication, persistence, or relapse and is of paramount importance. Several months of follow-up may be necessary for the detection of late relapses or metastatic infections. This guideline does not apply to studies of bacteremia or fungemia secondary to non-device-related, organ-based primary infections (e.g., pneumonia, urinary tract infection), which should be assessed in relation to the primary disorder.

Experimental infection models have long been recognized as an essential part of testing anti-infective therapies. A perfect animal model would be a model that satisfied not only scientific criteria, but ethical criteria as well. In the design and execution of such experiments, scientific and ethical considerations are not mutually exclusive, but should be convergent and therefore result in the optimal model.

The effect of the duration of treatment on clinical and bacteriological efficacy is generally poorly evaluated for antimicrobial agents. Infection model studies have to a large extent concentrated on endocarditis. In clinical trials systematic and well controlled studies are abundant in the field of urinary tract infections and streptococcal tonsillopharyngitis, but almost non-existent in other types of infections. Paradoxically, most of the infections studied by experimental models are uncommon in man and evaluation of optimal treatment periods for these by clinical trial is therefore difficult. In the evaluation of new antimicrobial agents, closer collaboration of experimental model and clinical trial investigators is required to design models of infections and clinical trials to evaluate optimal duration of treatment.

We examined the effect of azithromycin (CP-62,993), a new oral macrolide-like antibiotic, alone and in combination with rifampin, as treatment for experimental staphylococcal osteomyelitis. Clindamycin was used as a comparison drug. Rats (n = 10 to 15 per group) were infected by direct instillation of Staphylococcus aureus into the tibial medullary cavity. After 10 days, 21-day treatments with azithromycin (50 mg/kg of body weight, once daily, by the oral route), rifampin (20 mg/kg, once daily, subcutaneously), or clindamycin (90 mg/kg, three times daily, by the oral route) were started. The drugs were used singly or in combination (azithromycin plus rifampin or clindamycin plus rifampin). Peak azithromycin concentrations in bone were > 30 times higher than levels in serum, but the drug had little effect on final bacterial titers (5.13 +/- 0.46 log10 CFU/g of bone; for controls, 6.54 +/- 0.28 log10 CFU/g). Clindamycin was more active than azithromycin (3.26 +/- 2.14 log10 CFU/g of bone; 20% of sterilized bones), but rifampin was the most active single drug (1.5 +/- 1.92 log10 CFU/g; 53% of sterilized bones). Therapy with rifampin or clindamycin alone was associated with the emergence of resistance. Rifampin plus azithromycin (0.51 +/- 1.08 log10 CFU/g of bone; 80% of sterilized bones) and rifampin plus clindamycin (0.87 +/- 1.34 log10 CFU/g of bone; 66% of sterilized bones) were the most active regimens. Thus, azithromycin is ineffective as a single drug for the treatment of experimental staphylococcal osteomyelitis, despite high levels in bone that markedly exceeded the MIC, but it may be an attractive partner drug for rifampin.

Besides promoting nonspecific resistance to experimental infection, muramyl peptide immunomodulators also potentiate the effects of antimicrobial agents. These substances have been evaluated in combination with appropriate anti-infective agents in various models of bacterial, fungal, parasitic, and viral infection. For the combined regimens to be effective, the immunomodulator apparently must be administered prophylactically; anti-infective efficacy is then increased in situations where the muramyl peptide is capable of promoting at least some resistance to the infection independent of the antimicrobial agent. Adjunctive administration of the muramyl peptide may reduce the required dosages of potentially toxic antimicrobial agents and hence may lower the risk of toxic side effects. Because of the way in which they stimulate the inflammatory/immune systems, muramyl peptide immunomodulators may improve the outcome of therapy for infections in immunocompromised hosts. Initial clinical applications could involve the use of these immunomodulators in combination with antimicrobial agents as prophylaxis in high-risk individuals without overt infections.

The virulence of Haemophilus influenzae type c when inoculated intracisternally (i.c.) into rabbits was evaluated. Rabbits are relatively resistant to infection with H. influenzae type b, such that inocula of the order of 10(6-9) cfu are required to produce meningitis in this model. In contrast, fatal meningitis was produced in this study when 10(3) cfu of a type-c strain were injected i.c. into rabbits. Numbers of bacteria in cerebrospinal fluid (CSF) of control (untreated) animals generally increased to 10(7) cfu/ml. Increases in white blood cells, protein and lactate in the CSF were similar to those which had been observed during meningitis due to Streptococcus pneumoniae in rabbits. The infection was amenable to therapy with ampicillin 50 mg/kg given intravenously 12 h after infection. Numbers of bacteria in CSF were reduced to 2.2 x 10(3) cfu/ml (SEM 0.2 x 10(3)) at 8 h after treatment with a single dose of ampicillin. Two doses of ampicillin, given 12 and 20 h after infection, significantly increased the mean survival time. In contrast to previous experimental studies with rabbits, the penetration of ampicillin into the CSF was high--46 (SEM 10) % of the blood level. Since considerable replication of H. influenzae type c occurred within the CSF in this model, the nature of the meningeal damage produced was likely to be similar to that which takes place in man. Hence, H. influenzae type c meningitis in rabbits may provide a useful model in which therapeutic and other experimental studies of H. influenzae meningitis can be performed.

In this paper we describe our new results dealing with microwave industrial applicators used for drying of textile materials. We have designed and evaluated two different types of these applicators: open-resonator-type and waveguide-type one. We describe here basic models of the discussed applicators, results of numerical modelling and experimental evaluation as well. Prototype of microwave drying machine working at frequency 2.45 GHz is reported.

The concentration of a marginal population (35% drug addicts) in prisons necessitates systematic and rigorous screening for hepatitis B and hepatitis C in subjects at risk. In June 1998, a screening program was initiated to determine the prevalence of HBV and HBC infections in prisoners and to determine the incidence after 3, 6 and 12 months detention. The screening program was proposed to 900 prisoners in a Paris prison (Maison d'arrêt de Paris-La Santé) from June 3 to November 10, 1998. The program included hepatitis B and hepatitis C serology at incarceration. For prisoners who were seronegative for HCV at incarceration, a new HCV serology was proposed after 3, 6 and 12 months detention. It was postulated that HCV contamination could occur during incarceration (syringe sharing, tattooing). After one year of incarceration, no seroconversions for HCV were observed among the prisoners participating in this study. These findings should be interpreted with caution due to the particular detention conditions at the prison involved, raising important methodology interrogations concerning this type of survey.

Interleukin-8 (IL-8) is elevated in the cerebrospinal fluid (CSF) of patients with meningitis and is proposed to participate in subarachnoid-space pleocytosis. However, intracisternal injection of IL-8 into rabbits failed to induce indices typical of meningitis (leukocyte, tumor necrosis factor, or protein accumulation in the CSF or histopathological changes), indicating that merely increasing the CSF level of this chemokine is insufficient to induce inflammation in this anatomical site. IL-8 treatment did not affect inflammatory responses to subsequently intracisternally administered lipopolysaccharide (LPS). IL-8 was chemotactic for rabbit neutrophils in vitro, and subcutaneous injection of IL-8 (diluted in buffer or CSF) proved the in vivo activity of this peptide and suggested the absence of an IL-8 inhibitor in normal rabbit CSF. LPS-dependent pleocytosis was only slightly diminished by intracisternally administered murine anti-rabbit IL-8 monoclonal antibody (MAb) WS-4 but was dramatically reduced by intravenously administered MAb. Therefore, elevated CSF IL-8 levels may contribute to, but cannot solely account for, neutrophil influx into the subarachnoid space during meningitis. However, inhibition of IL-8 activity of the bloodstream side of the blood-brain barrier effectively reduces pleocytosis, indicating a central role of IL-8 in neutrophil influx into CSF during bacterial meningitis. Thus, inhibition of IL-8 is a possible therapeutic target for adjunct treatment of meningitis.

The purpose of the present study was to evaluate the combination of azithromycin and rifampicin on experimental chronic osteomyelitis due to Staphylococcus aureus. Alterations in bone bacterial titre, activity of tumour necrosis factor (TNF), a cytokine implicated in inflammation-induced bone pathology, and histopathological changes during infection and following antibiotic treatment were evaluated. Rats were infected with S. aureus by direct tibial inoculation and then randomized 56 days after infection to receive saline treatment or a combination of azithromycin and rifampicin (50 mg/kg po and 25 mg/kg sc respectively) once daily for 21 days. The combination of azithromycin and rifampicin was successful as determined by dramatic reduction in bone bacterial counts (approximately log 4 cfu), but regrowth of the organisms occurred suggesting that the duration of treatment was insufficient. TNF alpha mRNA and TNF activity were constantly elevated by approximately 20- and >200-fold, respectively, and remained elevated irrespective of antimicrobial treatment. Bone histology revealed extensive increase in bone turnover in both the infected and antibiotic treated bones with no difference being observed between the groups. This suggests that, in infected bone, the elevated TNF levels observed may be directly related to the bone pathology and both remain largely unchanged despite potent antibiotic therapy.

Surmmary The objective of adjunct anti-inflammatory therapy of bacterial meningitis is the containment of heightened inflammation caused by lysis of bacteria by antibiotics. This can be modelled by giving two consecutive intra-cisternal injections of lipopolysaccharide (LPS) to rabbits, the first at 0 h to induce inflammation to mimic that occurring during the proliferation of bacteria in the cerebrospinal fluid (CSF). and the second at 6 h to mimic inflammation subsequent to antibiotic-induced bacterial lysis. Injection of 2·5 ng of LPS induced pleocytosis at 4 h which was preceded by a peak of tumour necrosis factor (TNF) activity at 2 h. A subsequent injection of 25 ng of LPS at 6 h induced second peaks of pleocytosis and CSF TNF. Dexamethasone (1·5 mg/kg, i.v.) administered 15 min or 1 h before the second injection of LPS tended only to reduce CSF TNF, but effectively prohibited further pleocytosis. Brain TNFα mRNA levels were unchanged at 6 and 7 h after LPS injection, and were unaffected by dexamethasone. These results indicate that the subarachnoid space is distinct from the general circulation in that the TNF-producing cells present do not display a hypo-responsive state towards LPS as occurs when LPS is injected systemically. Furthermore, dexamethasone is able to attenuate the secondary inflammatory response resulting from a second LPS injection without eliminating a second peak of TNF activity.

The usefulness of scid mice bearing endogenous Pneumocystis carinii infection as a model for experimental chemotherapy was examined using standard compounds known to be effective against P. carinii. Trimethoprim/sulphamethoxazole was able to reduce pulmonary P. carinii cysts in a dose-dependent manner within the dose range studied (10/50 to 100/500 TMP/SMX mg/kg/d, bd, po, 5 days per week for 30 treatments). However, alterations in associated symptoms of infection (reduced body weight, increased lung weight, increased blood leucocytes and erythrocytes), was apparently not linearly dose-dependent. Blood and lung lavage fluid levels of sulphamethoxazole one hour post administration of trimethoprim/sulphamethoxazole was dose-dependent, but not linear with dose, and was apparently correlated to cyst reduction; trimethoprim was below the limit of detection at this time. Treatment of mice with 100/500 mg/kg/day trimethoprim/sulphamethoxazole required 2 weeks (bd for 10 days of treatment) before changes in indices of infection became significant. Pentamidine (20 mg/kg, sc, three times per week for 3 weeks) was nearly as effective as high-dose trimethoprim/sulphamethoxazole in reducing cysts, whereas lower doses were ineffective. Despite being unable to reduce pulmonary P. carinii infection, even low doses of pentamidine (6 or 2 mg/kg, sc, three times per week for 3 weeks) were able to reduce lung weights and blood leucocyte levels. This model of pulmonary P. carinii infections is amenable to chemotherapeutic intervention in an apparently dose-dependent fashion, and can be used to evaluate the capacity of compounds to eradicate P. carinii and resolve signs of infection.

Elevation of the environmental temperature appeared to counteract the temperature-depressing effects of urethane anesthetic and allowed rabbits intracisternally infected with Haemophilus influenzae type b to mimic the development of a fever following infection. Elevated core body temperature (greater than 39 degrees C) was associated with an inhibition of the growth of H. influenzae in cerebrospinal fluid (CSF) during the first 12 h postinfection, whereas bacterial growth was essentially unrestricted in rabbits with reduced (approximately 37 degrees C) body temperature. Bacterial densities 24 h postinfection were different, hyperthermic animals having log 6.0 +/- 0.4 CFU/ml of CSF and hypothermic rabbits having log 8.2 +/- 0.8 CFU/ml of CSF (P less than 0.05, Wilcoxon rank sum test). However, the growth of this bacterium in vitro, in either pooled rabbit CSF or brain heart infusion broth, was not inhibited at 39 degrees C. These results suggest that elevated body temperature associated with the development of fever during meningitis may be associated with restriction of the growth of H. influenzae in vivo but that this effect is apparently not due to an innate inability of the bacterium to grow at elevated temperatures.

Introduction Une EPP a ete initiee a l’hopital Cochin entre juin et decembre 2007 pour evaluer et optimiser les modalites de depistage et de prise en charge des patients chroniquement infectes par le VHC et le VHB. Methodes Apres elaboration d’une grille de recueil standardise, les modalites de depistage, de surveillance et de vaccination ont ete evaluees sur 154 dossiers consecutifs de patients infectes par le VIH et suivis en Medecine Interne et Maladies Infectieuses (14 dossiers par medecin). L’evaluation de la prise en charge des hepatites et des cirrhoses a porte sur l’etude de dossiers de patients chroniquement infectes par le VHC (84 dossiers) et le VHB (56 dossiers). Resultats Parmi les 154 dossiers de patients VIH+ etudies, le depistage du VHC et du VHB etait satisfaisant (96 % pour le VHC et 94 % pour le VHB). Chez les patients porteurs d’une 1re serologie negative, un controle a ete effectue dans les 3 ans suivant le test negatif dans 52 % des cas pour le VHC et 65 % des cas pour le VHB. Seuls 32 % des patients porteurs d’une serologie VHB initialement negative ont ete effectivement vaccines. L’evaluation de la maladie hepatique etait meilleure pour le VHC que pour le VHB : Genotype Echographie Avis hepatologue Evaluation fibrose * Evaluation fibrose Evaluation complete ** VHC 85 % 73 % 35 % 85 % 50 % 44 % VHB 7 % 69 % 51 % 13 % 41 % * Par PBH ou fibrotest ou fibroscan pour le VHC ; par PBH pour les VHB ADN+ ** Par PCR + Echographie + ALAT + Evaluation fibrose Les indications therapeutiques ont ete jugees atisfaisantes. Au stade de cirrhose, les patients VHC+ beneficiaient plus souvent d’une evaluation que les patients VHB+ : alpha-fœtoproteine (88 % vs 77 % pour le VHC et le VHB respectivement), Tp Conclusion Plusieurs axes d’amelioration ont ete collectivement definis : controle des serologies negatives chez les personnes a risque, ameliorer la vaccination contre le VHB. Chez les patients chroniquement infectes, une reevaluation de la fibrose tous les 3 ans et un bilan complet de cirrhose avec consultation d’hepatologie ont ete juges prioritaires.

As opposed to the testing of safety, the testing of the efficacy of antibiotics in animals is not specified in any directives or guidelines and not explicitly required by regulatory authorities. There exists, however, no doubt that in the evaluation of new compounds testing of both safety and efficacy forms an essential link between in vitro tests and clinical trials. It is inconceivable that clinicians would be prepared to conduct a trial in patients without evidence of the efficacy of the antibiotic in question in an appropriate animal model of infection. Both the models for testing safety and those for testing efficacy suffer from a number of shortcomings. If investigators are aware of these deficiencies and take them into account when interpreting the results, the predictive value of the models can be significantly enhanced.

The general principles of screening antibiotics for antimicrobial activity are similar to those for screening for other pharmacological effects. The system should be adapted to the specific character of the test substance and the objectives of the program. In the screening of beta-lactams, standard tests, such as determination of the MICs, effects of inoculum size or activity against systemic infection in mice, should be supplemented by less conventional studies on for instance activity against dormant bacteria or, in the case of penems or carbapenems, stability in the presence of kidney and lung dehydropeptidases.

The efficacies of the quinolones ciprofloxacin and pefloxacin alone and in combination with rifampin were compared with those of vancomycin alone and in combination with rifampin in a rat model of chronic osteomyelitis caused by methicillin-resistant Staphylococcus aureus. Neither the quinolones nor vancomycin alone was effective in reducing titers of organisms in bone after therapy, while rifampin alone was effective. All combination regimens with rifampin were more effective than the regimen with rifampin alone was, although these differences did not achieve statistical significance. Rifampin-resistant isolates were detected rarely. Quinolone-rifampin combination regimens may offer a nonparenteral option for the treatment of chronic osteomyelitis caused by methicillin-resistant S. aureus.

We studied the effects of ampicillin and anti-inflammatory agents on cerebrospinal fluid (CSF) protein patterns in rabbits with meningitis caused by Streptococcus pneumoniae. CSF proteins were analyzed in the acute phase of infection and during convalescence by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by two types of staining or by immunoblotting. During the acute phase a massive influx of serum albumin into the CSF was accompanied by the appearance of other proteins of high and low molecular weight. In untreated animals and animals given ampicillin alone or together with indomethacin, the abnormal pattern persisted for up to 30 d. Combined treatment with ampicillin and dexamethasone or oxindanac, a new nonsteroidal anti-inflammatory drug, partially prevented the alterations in CSF protein patterns. Reversion to normal CSF protein patterns was fastest in these two groups.

Rabbits with established staphylococcal endocarditis, injected twice at an interval of 2 h with either 0.5 mg of cloxacillin per kg or saline, were sacrificed 2.5 h after the second injection. Vegetations were excised, weighed, and cultured, and ultrathin sections were prepared and examined by light microscopy, transmission electron microscopy, and scanning electron microscopy. Several affected valves were examined histologically. Concentrations of cloxacillin in serum were determined 1 and 3 h after dosage. Staphylococci grown on membranes placed on agar containing 0.09 micrograms of cloxacillin per ml and in broth at the same cloxacillin concentration (one-third of the MIC) were examined by transmission electron microscopy. The mean numbers of CFU per gram of vegetations from control and treated rabbits were 2.28 X 10(10) and 1.31 X 10(10), respectively. Vegetations of treated rabbits contained staphylococci of normal size and form as well as organisms two to six times larger than normal with multiple cross walls. Larger bacterial cells were usually located in areas close to blood; cells of normal size were usually embedded in fibrin. The structures of these staphylococci and those grown on membranes in the presence of 0.09 micrograms of cloxacillin per ml were comparable but were different from those grown in broth containing this concentration of cloxacillin. Concentrations of cloxacillin in serum were 0.166 micrograms/ml at 1 h and 0.286 micrograms/ml at 3 h after dosage. The similarities in ultrastructure between staphylococci in vegetations of treated rabbits and staphylococci grown on membranes suggest that the vegetations contained approximately 0.09 micrograms of cloxacillin per g. Thus, antibiotic penetration from blood into vegetations and diffusion into fibrin were limited.

A number of semisynthetic bicyclomycin derivatives have been prepared by modifications at various sites of the molecule. The preparation, characterization and antimicrobial evaluation of the new compounds is described. In contrast to bicyclomycin itself, the new derivatives 48 and 58 are also active against Proteus species. Otherwise, the antibacterial potency of the bicyclomycin molecule was found to be very sensitive to structural changes.

The relative contribution of bacterial components to the induction of inflammation during Streptococcus pneumoniae meningitis is unknown. Several strains of pneumococci with differences in cell surface characteristics (capsule or cell wall) were compared for the effect on the inflammatory response evoked during infection of the cerebrospinal fluid (CSF) in vivo. The presence of bacterial capsular polysaccharide was not necessary for bacterial growth in CSF in vivo but correlated with greater CSF bacterial density. CSF inflammatory changes began to appear when the bacterial concentration exceeded 10(5) cfu/ml, regardless of the pneumococcal strain. CSF inflammatory changes could be invoked by cisternal instillation of 10(5)-10(6) cell equivalents of whole, heat-killed unencapsulated strains or their isolated cell walls but not by similar concentrations of heat-killed encapsulated strains or isolated capsular polysaccharide. Hypoglycorrhachia was observed only during inflammation caused by live bacteria. The inflammatory response characteristic of naturally acquired pneumococcal meningitis can be reproduced by challenge with both encapsulated and uncapsulated bacteria. The bacterial cell wall appears to be the most potent pneumococcal surface component in inducing CSF inflammation.

In continuation of our work on penem antibiotics, novel chiral (5R,6S)-2-(1′-aminoalkyl)-6-(hydroxyalkyl)-derivatives 1 have been synthesized by two essentially different strategies. Whereas the starting materials for 1a-f, azetidinones 2 and 5, were obtained from chiral building blocks (6-aminopenicillanic acid and L-threonine, resp.), the one for 1g, azetidinone 9, was derived from racemic 4-acetoxyazetidinone and, as chiral auxiliary, (2R)-2-mercaptopropan-1-ol. The 2-aminomethyl derivatives 1a (CGP 30 779) and 1f (CGP 31 608) proved the most potent compounds in the antibacterial tests in vitro and showed a well-balanced spectrum of activity by comparison with that of established β-lactams.

We studied the efficacy of penicillin and penicillin combined with streptomycin in the treatment of experimental endocarditis caused by viridans streptococci that are susceptible, tolerant, or relatively resistant to penicillin. Rabbits with experimental endocarditis were treated with procaine penicillin (1.5 X 10(5) U/kg) administered twice daily or with procaine penicillin (1.5 X 10(5) U/kg) plus streptomycin (20 mg/kg) administered twice daily for five days. Compared with control animals, animals treated with penicillin alone experienced a significant reduction (P less than .001) of colony forming units per gram of cardiac valve vegetations when infected with streptococci that are susceptible, tolerant, or resistant to penicillin. This antibiotic alone was less effective against streptococci that were tolerant or resistant to penicillin than against streptococci susceptible to the drug (P less than .01). The combination of penicillin and streptomycin was more effective therapy than was penicillin alone in animals with penicillin-tolerant or penicillin-resistant streptococci causing endocarditis (P less than .01). Penicillin-streptomycin therapy was less active against penicillin-resistant strains than against either penicillin-tolerant (P less than .04) or penicillin-susceptible (P less than .01) strains. The results of our study suggest that tolerance or relative resistance to penicillin in strains of viridans streptococci influences the response to therapy with penicillin alone or penicillin combined with streptomycin in the treatment of experimental endocarditis caused by viridans streptococci.

An NMOS DRAM controller for use in microcomputer systems based on the iAPX-86 and iAPX-286 microprocessor families or on the Multibus system bus is described. The controller provides complete support for dual-port memories and memories with error checking and correction. The controller has programmable attributes for configuring it to the particular requirements of the system. The controller uses parallel arbitration to minimize arbitration delay. A memory cycle will start on the same clock edge that samples a command if the cycle has been previously enabled. Novel logic and circuit design techniques have been used to achieve 16 MHz operation, 20 ns input setup time, and 35 ns output delay time.

A new group of chemical agents with pronounced antibacterial activities is presented. Different nitrothiazole derivatives, but not all, exhibit antibacterial activities similar to that of niridazole (AmbilharR), a nitrothiazolyl-imidazolidinone. Certain aerobic bacteria are moderately susceptible to these agents. The efficacy of these agents is almost comparable to that of ampicillin and tetracyline. It is much better than the efficacy of nitrofuran derivatives, the nitroimidazole derivatives being inactive. The mode of action of the nitrothiazole derivatives is bactericidal. Against anaerobic bacteria the nitrothiazole derivatives are unique, since the extremely low MIC's are not approached by any other of the nitro-compounds nor by any other of the common antibiotics tested, such as clindamycin, ampicillin and tetracycline. It is suggested that the nitrogroup of the nitrothiazole ring moiety represents the chemical structure responsible for their excellent antibacterial activities.

The antibacterial activities of niridazole (AmbilharR) and 12 other newly synthesized nitrothiazole derivatives were examined. Most of these compounds were active in vitro against Salmonella typhimurium (MICs 1-4 mg/l) and Bacteroides fragilis (MICs 0.015-0.03 mg/l). A therapeutic effect as determined by a reduction of bacterial counts per spleen of mice infected with Salm. typhimurium could only be achieved with those agents which displayed a similar side chain as niridazole, i.e. an imidazolidinone ring. Other nitrothiazole derivatives with a cleaved imidazolidinone ring as the side chain, although active in vitro, could not exert a reduction of bacterial counts in vivo. Similar results were obtained in mice infected with Bact. fragilis. Whereas niridazole and another nitrothiazole derivative with an imidazolidinone ring in the side chain were able to reduce the bacterial counts in a subcutaneous abscess, the derivative with a laminar side chain was inactive in vivo, although highly active in vitro.

We have studied the action of various antimicrobial agents in microbiological media and in human duodeno-pancreatic secretions. In the latter medium, clioquinol exhibited a rapid bactericidal effect on both growing and stationary bacteria at concentrations near its MIC. However, it was merely bacteriostatic in microbiological media, even at high concentrations. Phanquinone, chlorquinaldol, and, to a lesser extent, also chloramphenicol and trimethoprim likewise displayed enhanced bactericidal activity in duodeno-pancreatic secretions, but various other antibacterial agents did not. These findings suggest that duodeno-pancreatic secretions contain a factor augmenting the antibacterial activity of a number of drugs.

Bacterial adhesion to the constituents of nonbacterial thrombotic endocarditis (NBTE) is important in the pathogenesis of endocarditis. Subinhibitory concentrations (subMIC) of some antibiotics decrease bacterial adhesion to epithelial cells in vitro. We utilized an in vitro assay system to study the effect of subMIC of various antibiotics on streptococcal adhesion to a fibrin-platelet matrix (simulating NBTE). The results were (a) bacterial adhesion of Streptococcus sanguis and Streptococcus faecalis to NBTE was significantly reduced by vancomycin, penicillin, tetracycline, chloramphenicol and streptomycin (P less than 0.01 vs. controls) but not rifampin or trimethoprimsulfametrole; (b) the effect was dose-dependent and increased with duration of exposure to antibiotic; (c) reduction in bacterial adhesion did not correlate with altered retention by hydrophobic-interaction chromatography. This reduction in adhesion correlated with a diminished capacity of subMIC exposed Streptococcus sanguis (1/4 vancomycin minimum inhibitory concentration (MIC) X 4 h) to produce endocarditis in vivo. After intravenous inoculation of 10(6) colony-forming units of preincubated organisms into rabbits with traumatized aortic valves, 6 of 22 developed endocarditis vs. 17 of 22 controls (P = 0.03). These results may be relevant to prophylaxis of endocarditis since exposure of bacteria to subMIC of various antibiotics may reduce bacterial adherence both, to mucosal surfaces, and to damaged cardiac valves.

2-Heterocyclylmercaptoalkyl penems were synthesized and their in vitro potency was established. The compounds exhibit moderate to strong antibacterial activity against various Gram-positive and Gram-negative bacteria. Their antimicrobial activity is related to the nature of the heterocycle, the length of the hydrocarbon spacer between the 2-position of the penem nucleus and the mercapto group, and the substitution pattern of the C-6 position of the penem skeleton.

The antimicrobial activity of 5-chloro-2(2,4-dichlorophenoxy) phenol (triclosan, one of the active ingredients of Logamel®, Ciba-Geigy) was compared in vitro with that of other antimicrobials exclusively or occasionally used as topical agents in dermatology: hexachlorophene, clioquinol, chlorquinaldol. gentamicin, neomycin, nystatin, econazole, clotrimazole and salicylic acid. Upon determination of the MICs for 53 strains of aerobic and anaerobic bacteria, yeasts and fungi, triclosan was found to display a high degree of activity against most of the test organisms and to have the broadest spectrum of chemotherapeutically significant antimicrobial activity of the substances tested.

Using a rabbit model of experimental pneumonitis, the components on the surface of the pneumococcus that incite pulmonary inflammation were identified. Rabbits were challenged intratracheally with live pneumococci, capsular polysaccharide, purified cell walls, or cell wall subcomponents. Leukocytosis and elevation of protein concentration was quantitated in bronchial lavage fluid during the first 24 h after challenge. Of the pneumococcal surface components tested, cell wall preparations had the highest specific activity in inducing inflammation; abnormalities in bronchial lavage fluid cytochemistry appeared rapidly and in a dose-dependent manner. Cell wall building blocks and the products of penicillin-induced hydrolysis of the cell wall were also highly inflammatory, indicating that inflammation can be generated by disruption of the cell wall during lysis of bacteria by beta-lactam antibiotics. Administration of inhibitors of arachidonic acid metabolism suggested that inhibition of the lipoxygenase pathw...

Subinhibitory MICs (sub-MICs) of several cephalosporins significantly reduced the enterochelin production of Klebsiella pneumoniae 327 grown under iron-depleted conditions and also reduced capsule formation regardless of iron availability. The surface hydrophobicity of K. pneumoniae 327 increased significantly when the bacteria were grown in either iron-sufficient or iron-depleted media in the presence of sub-MICs of all the cephalosporins used in this study. Antisera raised against a non-encapsulated K. pneumoniae strain caused rapid agglutination of K. pneumoniae 327 grown in the presence of sub-MICs of the cephalosporins but no agglutination of the same strain grown in drug-free media. The results indicated that the cephalosporins reduced enterochelin production and also capsule formation to the extent that noncapsular surface antigens were exposed, with possible significant consequences in vivo.

Summary: Nongrowing bacteria evade the bactericidal activity of βbT-lactam antibiotics. We sought to determine if slow growth rate also alters bactericidal activity. The bactericidal activity of two βbT-lactams on Escherichia coli grown in glucose limited chemostats was compared for generation times ranging from 0·7 to 12 h. The degree of killing varied with drug structure and with E. coli strain. However, all killing rates were a constant function of the bacterial generation time: slowly growing bacteria became progressively more phenotypically tolerant to βbT-lactam antibiotics as the generation time was extended.

The adhesion of radiolabeled Escherichia coli (strain SS142) to monolayers of Intestine 407, a human epithelioid tissue culture cell line, was investigated. In this assay the adhesion of bacteria grown in the presence of subminimal inhibitory concentrations of tetracycline, clindamycin,, or trimethoprim-sulfametrole was reduced in a manner that was dose dependent. In contrast, at such concentrations nalidixic acid enhanced the adhesion of this bacterial strain, and other antibiotics-e.g., penicillin G, ampicillin, mecillinam, cephacetrile, cephalexin, cefotaxime, chloramphenicol, and streptomycin-did not affect its adhesiveness.

Niridazole (Ambilhar) and three other newly synthesized nitrothiazole derivatives were highly active against 19 microaerophilic campylobacters (minimum concentration required to inhibit 50% of strains [MIC50], 0.0075 to 0.015 mg/liter). There were, however, considerable differences in the susceptibility among strains tested, and one nitrothiazole derivative was rather inactive (MIC50, 2 mg/liter). Nitroimidazole derivatives, such as metronidazole and tinidazole, were less active (MIC50, 2 and 4 mg/liter, respectively). The nitrofuran derivatives, such as nitrofurazone and nitrofurantoin, were also less active (MIC50, 1 mg/liter). Niridazole and another potent nitrothiazole derivative killed the campylobacters rapidly at low concentrations. In contrast, much higher concentrations of metronidazole were required to achieve bactericidal values.