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T O'Reilly

Publications and source records attributed to T O'Reilly.

At least 37 records · Page 2Linked to original sources
PubMed1997

Local expression of tumor necrosis factor alpha in an experimental model of acute osteomyelitis in rats.

The inflammatory response associated with Staphylococcus aureus osteomyelitis results in extensive bone damage characterized by apparent increases in bone resorption and formation. These results suggest an increased local release of agents capable of modulating bone remodelling. Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine proposed to play an important role both in normal bone remodelling and in bone diseases; however, its potential role in osteomyelitis is unclear. This study evaluated changes in bone TNF levels during infection, using a rat model of acute osteomyelitis due to S. aureus. Following direct tibial infection, bacterial counts in bone were persistently high (approximately 6 log10 CFU/g of bone over 63 days) and bone weights increased. TNF activity was undetectable in uninfected bone (<0.01 ng/g of bone) but dramatically higher in infected bone (up to 5.2 +/- 3.5 ng/g of bone). Although TNF-alpha mRNA was weakly detected in uninfected bone, osteomyelitis was associated with up to 37-fold increases in expression of both the 1.6- and 2.4-kb transcripts. Both TNF activity and mRNA transcript levels remained elevated throughout the course of infection. TNF-alpha mRNA detected by in situ hybridization was present in osteoblasts as well as in populations of marrow cells and/or inflammatory infiltrate cells. Histopathology of infected bone indicated extensive bone resorption and adjacent areas of formation that were associated with cells expressing TNF-alpha mRNA. These data suggest that the elevated TNF levels induced by experimental infection may be directly related to changes in the histology of bone during osteomyelitis.

Acute Disease↗
PubMed1996

Maintenance of intestinal epithelium structural integrity and mucosal leukocytes during chemotherapy by oral administration of muramyl tripeptide phosphatidylethanolamine.

The systemic administration of doxorubicin (DXR) decreases the number of epithelial cells and leukocytes in the small intestine of mice. Oral administration of muramyl tripeptide phosphatidylethanolamine (MTP-PE) prevented both disruption of intestinal architecture, and a decrease in the number of macrophages, and it induced the expression of IL-6, G-CSF, GM-CSF, and TNF-alpha in the intestinal tissue. The data suggest that the oral administration of MTP-PE can prevent chemotherapy-induced toxicity to the intestinal mucosa and hence infections due to translocation of aerobic bacteria from the intestine to the blood.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1995

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy.

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.

Animals↗
PubMed1995

Dexamethasone treatment of lipopolysaccharide-induced meningitis in rabbits that mimics magnification of inflammation following antibiotic therapy.

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 TNF alpha 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.

Animals↗
PubMed1995

Relevance of animal models for chronic bacterial airway infections in humans.

Animal models of chronic bacterial airway infections are limited in relevance to human infection, not only because of limitations present in all animal models (e.g., abnormal sequence of pathologic events, artificial imposition of infection involving large inocula, dissimilar host pharmacokinetic attributes), but especially because underlying disease (chronic obstructive pulmonary disease, or COPD) is usually absent. A major problem in establishing chronic lung infection models is the rapid clearance of bacteria instilled into the drugs; this can be overcome by encasing bacteria into agar beads to restrict phagocytosis. Despite these limitations, animal models based upon agar bead-encased inocula have provided persistent infections resulting in lung pathology and high humoral immune responses similar to that observed in patients with COPD. Such models have illuminated some aspects of the virulence of the bacteria, the involvement of bacterial exoenzymes in promoting lung damage, the potential of vaccination to restrict infectious exacerbations, and the activity of subminimal inhibitory concentrations of antibiotics in reducing lung damage by inhibiting exoenzyme release. Animal models have also shown that anti-inflammatory therapy may be effective in reducing inflammation-associated lung damage. Despite the limitations of chronic lung infection models, they may provide insight into pathologic events and positive therapeutic intervention for lung infections of patients with COPD.

Animals↗
PubMed1994

Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes.

Several chemotactic agonists including interleukin-8 (IL-8) and related cytokines have been shown to activate and attract leukocytes via seven-transmembrane domain, GTP-binding protein-coupled receptors. A cDNA clone, LESTR, encoding a protein of 352 amino acids, corresponding to a novel receptor of this type, was isolated from a human blood monocyte cDNA library. The sequence of the deduced protein, LESTR (leukocyte-derived seven-transmembrane domain receptor), has 92.6% identity with that of a recently reported bovine neuropeptide Y (NPY) receptor, boLCR1 (Rimland, J., Xin, W., Sweetnam, P., Saijoh, K., Nestler, E. J., and Duman, R. S. (1991) Mol. Pharmacol. 40, 869-875). LESTR, however, is more similar (> 34%) to the IL-8 receptors, IL-8R1 and IL-8R2, than to several NPY receptors of different origin (< 20%). In the monocyte library, LESTR cDNA fragments were about 20 times as frequent as cDNA coding for IL-8R1 and IL-8R2, and much higher levels of LESTR- than IL-8R-specific mRNA were found in human blood neutrophils and lymphocytes. LESTR transcripts, by contrast, were low or undetectable in several neuroblastoma cell lines that are widely used to study NPY functions. Transfected cells expressing high levels of LESTR mRNA did not bind radiolabeled NPY, IL-8, NAP-2, GRO alpha, PF4, IP10, MCP-1, MCP-3, MIP-1 alpha, HC14, I309, RANTES, C3a, or LTB4. NPY also failed to bind to neutrophils, monocytes, and lymphocytes, to elicit responses in vitro such as Ca2+ changes, shape change, chemotaxis, enzyme release, and the respiratory burst, and to induce leukocyte accumulation upon injection in rats and rabbits. Although the ligand for LESTR could not be identified among a large number of chemotactic cytokines, the high expression in white blood cells and the marked sequence relation to IL-8R1 and IL-8R2 suggest that LESTR may function in the activation of inflammatory cells.

Amino Acid Sequence↗
PubMed1994

Isolation and in-vitro and in-vivo characterisation of a mutant of Pseudomonas aeruginosa PAO1 that exhibited a reduced postantibiotic effect in response to imipenem.

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.

Acetylglucosamine↗
PubMed1993

Efficacy of antimicrobial agent treatment in relation to treatment regimen: experimental models and clinical evaluation.

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.

Animals↗
PubMed1992

Enhancement of the effectiveness of antimicrobial therapy by muramyl peptide immunomodulators.

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.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Experimental rabbit model of meningitis produced by Haemophilus influenzae serotype c.

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.

Ampicillin↗
PubMed1992

Effect of haemin limitation on the cytochrome complement and glucose metabolism of non-typable Haemophilus influenzae.

Haemophilus influenzae grown to exponential phase or stationary phase in medium with a low initial concentration of haemin (0.25 microgram/ml) was virtually devoid of cytochromes. Compared with bacteria grown in the presence of excess haemin (10 micrograms/ml), the haemin-limited organisms failed to respire formate and succinate and, generally, the respiratory rates with other substrates were reduced. However, growth rates were not affected by the haemin supply. Haemin-limited growth was associated with a reduced efficiency of glucose utilisation, in terms of glucose growth yields, and affected the net levels of excreted organic acids. Haemin limitation resulted in reduced acetate and increased succinate accumulation in the culture medium and the novel presence of D-lactate. These results indicate that, in contrast to the phenotype expressed in vitro during conventional cultivation of H. influenzae, the haemin-limited phenotype, which may be expressed in vivo, is characterised by a lack of cytochromes and a shift towards a more anaerobic type of metabolism.

Bronchiectasis↗
PubMed1992

Relationship between antibiotic concentration in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: azithromycin compared with clindamycin and rifampin.

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.

Animals↗
PubMed1992

Elevated body temperature restricts growth of Haemophilus influenzae type b during experimental meningitis.

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.

Animals↗
PubMed1991

Phenotypic variation in the outer membrane protein composition of Actinobacillus (Haemophilus) pleuropneumoniae: non-specific effect of exogenous pyridine nucleotide supply.

Actinobacillus pleuropneumoniae, grown in batch culture, was provided with pyridine nucleotides at concentrations that limited the final growth yield (pyridine nucleotide-deficient cultures) or did not determine the final extent of growth (pyridine nucleotide-sufficient cultures). Sarkosyl-extracted outer membranes from stationary phase, pyridine nucleotide-sufficient organisms contained 23,000 Mr and 43,000 Mr polypeptides that were absent (23,000 Mr) or barely detectable (43,000 Mr) in outer membranes from stationary phase, pyridine nucleotide-deficient organisms or exponential phase organisms. When growth ceased due to exhaustion of pyridine nucleotide, the ratio of the major outer membrane polypeptides (31,000, 38,000 and 69,000 Mr) was altered, becoming more like the ratio found with exponential phase organisms. Similar results were obtained when growth ceased due to glucose exhaustion at low biomass concentrations demonstrating that diverse nutrient deprivations can induce similar changes in outer membrane protein profile. All of these polypeptides were recognized by porcine immune sera indicating their production by A. pleuropneumoniae growing in vivo.

Actinobacillus pleuropneumoniae↗
PubMed1991

Rat model of chronic lung infections caused by non-typable Haemophilus influenzae.

Patients with chronic obstructive pulmonary disease (COPD) often have chronic or recurrent pulmonary infections with non-typable Haemophilus influenzae. A model of these infections exploited agar bead vehicles to protect the inoculum from rapid clearance, and a chronic lung infection of at least 42 days duration was established in rats. This infection induced increases in serum IgG titres to outer-membrane (OM) and lipo-oligosaccharide (LOS) antigens; immunoblotting demonstrated that this humoral response was directed partly against the outer-membrane proteins (OMPs). Lung lavage fluid also contained an increased titre of IgG antibodies to OM and LOS 42 days after infection. Antibodies produced during infection with one strain of H. influenzae cross-reacted with OMPs from another, non-typable H. influenzae strain. Despite their encasement in agar beads, pulmonary H. influenzae remained susceptible to amoxycillin. This model of chronic pulmonary infections due to non-typable H. influenzae appears to resemble the situation in COPD patients and may be useful for experimental therapeutic studies.

Animals↗
PubMed1990

Remarks on the screening of antibiotics for antibacterial activity.

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.

Animals↗
PubMed1990

Animal models as predictors of the safety and efficacy of antibiotics.

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.

Animals↗