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PubMed2002

The efficacy of amine fluoride/stannous fluoride in the suppression of morning breath odour.

BACKGROUND: Breath odour is a complaint encountered worldwide, often linked to microbial overload in the oral cavity. This double blind, crossover, randomised study assessed the efficacy of several antiseptic mouthrinses or slurry vs. a control solution in the prevention of morning bad breath during an experimental period of 7 days without mechanical plaque control. METHODS: Sixteen dental students with a healthy periodontium abolished, after a thorough professional cleaning, all means of mechanical plaque control during five experimental periods of 7 days, interleaved by washout periods of at least 3 weeks. During each experimental period, as the only oral hygiene measure, the students rinsed twice a day with one of the following formulations (in a randomised order): a 0.2% chlorhexidine-alcohol mouthrinse (CHX-Alc), a 0.05% CHX + 0.05% cetylpyridinium chloride + 0.14% zinc lactate mouthrinse (CHX-CPC-Zn), an amine fluoride/stannous fluoride (125 ppm F-/125 ppm F-) containing mouthrinse (AmF/SnF2Mr), a slurry of a tooth paste (AmF/SnF2Sl) containing amine fluoride (350 ppm F-) and stannous fluoride (1050 ppm F-) and a placebo solution (placebo). At days 0, 3 and 7, morning breath was scored via VSC level measurements of the mouth air, and organoleptic ratings of the mouth air and tongue coating. At the same visits both the degree of gingival inflammation and the de novo plaque formation were rated. At the end of each period a questionnaire for subjective ratings was completed and microbiological samples were taken from the tongue dorsum, the saliva and the supragingival plaque for anaerobic and aerobic culturing. RESULTS: Although oral hygiene during the experimental periods was limited to rinsing, bad breath parameters systematically improved (P < 0.001) with the three mouthrinses (CHX-Alc, CHX-CPC-Zn, AmF/SnF2Mr), with a superiority of the CHX-CPC-Zn solution when only VSC values were considered (P < 0.003). The AmF/SnF2 slurry and the placebo solution showed only minor changes with time. The three mouthrinses reduced significantly (P < 0.001) the bacterial load (aerobic & anaerobic) in the saliva (>or= 0.5 log reduction with a superiority (P < 0.005) for the CHX-Alc when compared to the two others). Changes in the bacterial load on the tongue dorsum could only be detected for the CHX-Alc solution (0.5 log). The antibacterial effect of the placebo solution and the slurry were negligible. The composition of microflora on the other hand did not reveal significant changes. The de novo supragingival plaque formation was significantly (P < 0.05) inhibited by the three mouthrinses with a slight superiority for the CHX-Alc solution. The degree of gingival inflammation at day 7 remained low (< 0.16) for all products. The CHX-Alc solution scored significantly worse for the subjective evaluation (questionnaires) concerning taste and sensitivity of tongue). CONCLUSIONS: The results of this study demonstrate that morning breath odour can be successfully reduced by the sole twice daily use of CHX-Alc, CHX-CPC-Zn or AmF/SnF2Mr mouthrinses, which all significantly reduced the bacterial load in the saliva and retarded the de novo plaque formation.

Adult↗

PubMed2005

Therapeutic efficacy of high-dose intravenous immunoglobulin in Mycobacterium tuberculosis infection in mice.

Intravenous immunoglobulin (IVIg) is used to treat patients with primary antibody deficiencies and, at high doses, to treat a range of autoimmune and inflammatory disorders. With high-dose IVIg (hdIVIg), immunomodulatory mechanisms act on a range of cells, including T cells, B cells, and dendritic cells. Here, we demonstrate that the treatment of M. tuberculosis-infected mice with a single cycle of hdIVIg resulted in substantially reduced bacterial loads in the spleen and lungs when administered at either an early or late stage of infection. Titration of the IVIg showed a clear dose-response effect. There was no reduction in bacterial load when mice were given equimolar doses of another human protein, human serum albumin, or maltose, the stabilizing agent in the IVIg preparation. HdIVIg in vitro had no inhibitory effect on the growth of M. tuberculosis in murine bone marrow-derived macrophages. In addition, the effect of hdIVIg on bacterial loads was not observed in nude mice, suggesting the involvement of conventional T cells. Analysis of T cells infiltrating the lungs revealed only small increases in CD8(+) but not CD4(+) T-cell numbers in hdIVIg-treated mice. The mechanism of action of hdIVIg against tuberculosis in mice remains to be determined. Nevertheless, since hdIVIg is already widely used clinically, the magnitude and long duration of the therapeutic effect seen here suggest that IVIg, or components of it, may find ready application as an adjunct to therapy of human tuberculosis.

Animals↗

PubMed1986

Studies on microorganisms secured from different organs of slaughtered sheep with special reference to the microbial load in certain muscles.

A total of 312 samples collected from different organs and muscles of dead, disabled, diseased, dying, and normal carcasses of sheep were examined bacteriologically to determine the different species of microorganisms as to their public health significance. In addition, the aerobic plate count (APC) and most probable number (MPN) coliform/g were determined of Musculus biceps brachii, Musculus quadriceps femoris, and Musculus longissimus dorsi. The mean bacterial load was higher in summer than in winter in dead and in normal sheep. Moreover, the APC was higher in winter 3 hours after slaughtering than after 24 h cooling. The bacterial load decreased in that order in the muscles of dead, disabled, diseased, and dying sheep carcasses. The lowest bacterial load was recorded in the Musculus longissimus dorsi. The most predominant isolates recovered from different organs and muscles were Escherichia coli (60), staphylococci (33), Proteus vulgaris (12), Enterobacter aerogenes (11), Corynebacterium ovis (9), Alcaligenes faecalis (7), Actinomyces israelii (5), Citrobacter freundii (4), pneumococci (3), and enterococci (2). The importance is discussed of the isolated strains as zoonotic agents and for assessing the hygienic meat quality.

Animals↗

PubMed2006

[Value of serum procalcitonin in diagnosing bacterial lower respiratory tract infections in people with exacerbation of Chronic Obstructive Pulmonary Disease].

OBJECTIVE: To investigate the changes and clinical implications of serum procalcitonin in exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: We have evaluated PCT measurement in 45 patients with an exacerbation of COPD (group A) and 25 patients with stable COPD (group B), quantitative sputum culture was performed, too. PPMs were only regarded as significant if they reached a growth of > or =10(7) cfu/mL, indicating the presence of bacterial infection. RESULTS: In patients with an exacerbation, 15 patients, sputum yielded a high (> or =10(7) cfu/mL) bacterial load (group A1), 30 patients, sputum yielded a low (<10(7) cfu/mL) bacterial load or a negative bacterial culture (group A2). The levels of procalcitonin in sera from patients of group A1 were significantly higher than those from group A2 and group B [0.24 (0.17, 0.28) microg/L vs. 0.125 (0.10, 0.18) microg/L vs. 0.12 (0.10, 0.145) microg/L, P= 0.000, 0.000]. The levels of procalcitonin in sera from patients of group A2 were similar to those from group B (P>0.05). Using a cut-off point of 0.155 microg/L for PCT, the sensitivities and specificities for bacterial infection in patients with an exacerbation of COPD were 93.3% and 60% respectively. CONCLUSION: Serum procalcitonin measurements in patients of an exacerbation of chronic obstructive pulmonary disease play a role in the diagnosis of bacterial infection.

Aged↗

PubMed2005

Bacteriospermia in extended porcine semen.

Bacteriospermia is a frequent finding in freshly extended porcine semen and can result in detrimental effects on semen quality and longevity if left uncontrolled. The primary source of bacterial contamination is the boar. Other sources that have been identified include environment, personnel, and the water used for extender preparation. A 1-year retrospective study was performed on submissions of extended porcine semen for routine quality control bacteriological screening at the University of Pennsylvania. Out of 250 sample submissions, 78 (31.2%) tested positive for bacterial contamination. The most popular contaminants included Enterococcus spp. (20.5%), Stenotrophomonas maltophilia (15.4%), Alcaligenes xylosoxidans (10.3%), Serratia marcescens (10.3%), Acinetobacter lwoffi (7.7%), Escherichia coli (6.4%), Pseudomonas spp. (6.4%), and others (23.0%). Prudent individual hygiene, good overall sanitation, and regular monitoring can contribute greatly in controlling bacterial load. Strategies that incorporate temperature-dependent bacterial growth and hyperthermic augmentation of antimicrobial activity are valuable for effective control of susceptible bacterial loads. Aminoglycosides remain the most popular antimicrobial class used in porcine semen extenders, with beta-lactam and lincosamide use increasing. With the advent of more novel antimicrobial selection and semen extender compositions in swine, prudent application and understanding of in vitro pharmacodynamics are becoming paramount to industry success in the use of this breeding modality.

Animals↗

PubMed2003

Association of INOS, TRAIL, TGF-beta2, TGF-beta3, and IgL genes with response to Salmonella enteritidis in poultry.

Several candidate genes were selected, based on their critical roles in the host's response to intracellular bacteria, to study the genetic control of the chicken response to Salmonella enteritidis (SE). The candidate genes were: inducible nitric oxide synthase (INOS), tumor necrosis factor related apoptosis inducing ligand (TRAIL), transforming growth factor beta2 (TGF-beta2), transforming growth factor beta3 (TGF-beta3), and immunoglobulin G light chain (IgL). Responses to pathogenic SE colonization or to SE vaccination were measured in the Iowa Salmonella response resource population (ISRRP). Outbred broiler sires and three diverse, highly inbred dam lines produced 508 F1 progeny, which were evaluated as young chicks for either bacterial load isolated from spleen or cecum contents after pathogenic SE inoculation, or the circulating antibody level after SE vaccination. Fragments of each gene were sequenced from the founder lines of the resource population to identify genomic sequence variation. Single nucleotide polymorphisms (SNP) were identified, then PCR-RFLP techniques were developed to genotype the F1 resource population. Linear mixed models were used for statistical analyses. Because the inbred dam lines always contributed one copy of the same allele, the heterozygous sire allele effects could be assessed in the F1 generation. Association analyses revealed significant effects of the sire allele of TRAIL-StyI on the spleen (P <0.07) and cecum (P <0.0002) SE bacterial load. Significant effects (P <0.04) were found on the cecum bacterial load for TGF-beta3-BsrI. Varied and moderate association was found for SE vaccine antibody response for all genes. This is the first reported study on the association of SNP in INOS, TRAIL, TGF-beta2, TGF-beta3, and IgL with the chicken response to SE. Identification of candidate genes to improve the immune response may be useful for marker-assisted selection to enhance disease resistance.

Animals↗

PubMed2003

Dietary fish oil impairs primary host resistance against Listeria monocytogenes more than the immunological memory response.

The primary objective of this study was to determine whether dietary (n-3) polyunsaturated fatty acids (PUFA) impair the ability of mice to generate an immunological memory response against the bacterial pathogen, Listeria monocytogenes. Weanling BALB/c female mice were fed for 28 d one of two semipurified high fat diets containing either lard or refined menhaden fish oil, rich in long-chain (n-3) PUFA. Mice were immunized with 10(4) or 10(3) colony forming units (cfu) bacteria. Thirty-five days later, these immune mice and age-matched naïve (i.e., unimmunized) mice were challenged with 10(5) cfu bacteria. Three days postchallenge, bacterial clearance was determined. Compared with lard-fed mice, naïve mice in the fish oil treatment group had higher bacterial loads in their liver and spleen (P < 0.001). When mice were immunized with 10(4) cfu bacteria before rechallenge with 10-fold more bacteria, both lard- and fish oil-fed mice had significantly lower bacterial loads in their liver and spleen (e.g., approximately 2 log(10); P < 0.001) compared with their naïve counterparts. However, when the immunization dose was reduced to 10(3) bacteria, a modest diet treatment effect was observed, such that compared with immune lard-fed mice, immune fish oil-fed mice had significantly greater bacterial loads in their liver and spleen (i.e., approximately 0.5 log(10); P < 0.01). These data demonstrate for the first time that although dietary (n-3) PUFA can significantly impair host resistance to a primary as well as a secondary L. monocytogenes infection, the impairment of the immunological memory response is much less severe.

Animals↗

PubMedDate not supplied

Factors influencing phagocytosis of Salmonella typhimurium by macrophages in murine schistosomiasis.

Macrophages from Schistosoma mansoni-infected mice showed depressed capacity to increase the phagocytosis in the presence of a high bacterial load, due to a reduced involvement of these cells in phagocytosis and to a deficient ability to increase the number of phagocytosed bacteria. Normal and Salmonella-infected mice increased their phagocytic capacity when exposed to a high bacterial load. Antibody to Salmonella increased the phagocytic capacity of macrophages from Schistosoma-infected mice due to an increase in the number of bacteria phagocytosed but caused no modification in the number of macrophages engaged in phagocytosis. Our data indicate that macrophages from Schistosoma-infected mice work close to their functional limit, since no increase in phagocytosis was observed after increasing the bacterial load. Specific antibodies can improve their phagocytic capacity and, therefore, could help clearing concurrent infection.

Animals↗

PubMed1996

Combined effect of gamma-irradiation and conventional cooking on Aeromonas hydrophila in meatball.

Irradiation combined with a conventional cooking procedure was applied to meatball and the effects on bacterial load and inoculated Aeromonas hydrophila were determined. Meatball samples were irradiated by using a 60Co source at the dose levels of 0, 0.30, 0.75, 1.50, 2.50 kGy and cold stored at 4 +/- 1 degrees C for 7 days. Bacterial load and the count of A. hydrophila decreased when the irradiation dose level increased. A minimum inhibition effect was found at the dose of 0.30 kGy. Irradiation in combination with a conventional cooking procedure was found to be more effective in reducing A. hydrophila and the bacterial load in meatball. This study indicated that a dose of 0.75 kGy was sufficient to destroy approximately 10(4) cfu/g of A. hydrophila in meatball.

Aeromonas hydrophila↗

PubMed2001

Microbiological, sensory, and electronic nose evaluation of yellowfin tuna under various storage conditions.

Microbiological assessment, sensory evaluation, and electronic nose (AromaScan) analysis were performed on yellowfin tuna stored at 0, 4, 10, and 22 degrees C for 0, 1, 3, 5, and 9 days. Fish color, texture, appearance, and odor were evaluated by a trained sensory panel, while aroma-odor properties were evaluated using an AromaScan. Bacterial enumeration was performed using plate count agar containing 1.5% NaCl. Tuna fillets stored at 22 degrees C for 3 days or longer had a bacterial load of over 10(7) CFU/g and were rated not acceptable for consumption (grade C) by the sensory panel. Tuna fillets stored at 4 degrees C for 9 days or 10 degrees C for over 5 days were rated as grade C products and also had a bacterial load of over 10(7) CFU/g. The change in fish quality as determined by AromaScan followed increases in microbiological counts in tuna fillets, indicating that bacterial load can serve as a useful and objective indicator of gross spoilage. Electronic nose devices can be used in conjunction with microbial counts and sensory panels to evaluate the degree of decomposition in tuna during storage.

Animals↗

PubMed1992

Chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex infection induced in mice.

Newly synthesized benzoxazinorifamycin, KRM-1648, was studied for its in vivo anti-Mycobacterium avium complex (MAC) activities. When the MICs were determined by the agar dilution method with Middlebrook 7H11 agar medium, KRM-1648 exhibited similarly potent in vitro antimicrobial activities against the MAC isolated from AIDS and non-AIDS patients, indicating possible usefulness of KRM-1648 against AIDS-associated MAC infections. KRM-1648 exhibited potent therapeutic activity against experimental murine infections induced by M. intracellulare N-260 (virulent strain) and N-478, which has much weaker virulence. Similarly, KRM-1648 exhibited an excellent therapeutic efficacy against M. intracellulare infection induced in NK-cell-deficient beige mice (as a plausible model for AIDS-associated MAC infection), in which a much more progressed state of gross lesions and bacterial loads at the sites of infection were observed. When the infected beige mice were killed at weeks 4 and 8, obvious therapeutic efficacy was seen on the basis of reduction in the incidence and degree of lung lesions and bacterial loads in the lungs and spleen with infections due to M. intracellulare N-241, N-256, and N-260. In this case, the efficacy was the highest in N-260 infection, followed by strain N-241. When mice were observed until infection-induced death, survival time of the infected beige mice was found to be prolonged by KRM treatment. However, KRM-1648 was not efficacious in suppressing the progression of pulmonary lesions and the increase in bacterial loads at the sites of infection, including lungs and spleen, at the late phase of infection. This may imply some difficulty with chemotherapy for AIDS-associated MAC infection, even with KRM-1648 treatment, which has excellent in vitro and in vivo anti-MAC activities, as shown in present study.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Quantities of Yersinia pestis in fleas (Siphonaptera: Pulicidae, Ceratophyllidae, and Hystrichopsyllidae) collected from areas of known or suspected plague activity.

We used a quantitative competitive polymerase chain reaction (PCR) (QC-PCR) to determine bacterial loads in 669 fleas collected in areas of confirmed and suspected plague epizootics. Fleas were collected out of rodent burrows (67.9%) and off of captured animals (24.1%) and rodent carcasses (8.1%). An initial PCR screening assay indicated that 12.1% (81/669) of all fleas were positive for Yersinia pestis. Fleas collected from burrows had significantly lower (chi2 = 264.9, P < 0.0001) infection rates (6.8%) but significantly higher (Student t-test, P < 0.0001) bacterial loads (mean = 10(5.6) Y. pestis per flea) than fleas collected off of rodent carcasses (infection rate = 92.6%; mean bacterial load = 10(4.8) Y. pestis per flea). None of the fleas collected off of captured animals were positive for Y. pestis by PCR, although seven of the 176 captured animals were serologically positive for Y. pestis.

Animals↗

PubMed2001

Role of IFN-gamma in bacterial containment in a model of intra-abdominal sepsis.

Interferon-gamma (IFN-gamma) is a specific activator of macrophage function and plays a critical role in the host immune defense to bacterial infection. In this study we examined the role of IFN-gamma in the regulation of bacterial load in the cecal ligation and puncture (CLP) model of intra-abdominal sepsis in the rat. In initial studies, levels of IL-12, MCP-1, and IFN-gamma were measured in the peritoneal lavage fluid 24 and 48 h after CLP. IL-12 and MCP-1 levels were both significantly increased at 24 h after CLP compared to sham controls and this difference was maintained at 48 h after CLP. Interestingly, IFN-gamma levels were not significantly increased 24 h after CLP, but were increased at 48 h after CLP. These results clearly suggest that although an inflammatory response had occurred 24 h post-surgery, with increases in the proinflammatory cytokine IL-12 and the potent chemotactic agent MCP-1, levels of IFN-gamma in CLP rats were similar to sham controls. To further investigate the role of IFN-gamma on the development of sepsis we examined the effect(s) of administering anti-IFN-gamma antibody on bacterial load after CLP. We show that use of anti-IFN-gamma antibody can significantly decrease bacterial load in the peritoneum. The mechanism of the effect(s) of anti-IFN-gamma is probably by increasing intestinal adhesions to seal the cecum and reduce bacterial movement into the peritoneum.

Animals↗

PubMed1997

Experimental lobar pneumonia due to penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae in immunocompetent and neutropenic rats: efficacy of penicillin and teicoplanin treatment.

Lobar pneumonia models were established in rats by intratracheal inoculation of either penicillin-susceptible (immunocompetent model) or penicillin-resistant (immunocompetent and neutropenic models) Streptococcus pneumoniae. Untreated animals maintained a relatively high bacterial load in the lungs but only occasionally developed bacteraemia or pleurisy. The infection was rarely fatal in immunocompetent rats, but immunocompromised rats frequently died. Treatment i.m. with 10,000 IU/kg of procaine penicillin G (12 h after infection then bid for 3 days) or with a single i.v. dose of 5 or 10 mg/kg of teicoplanin significantly reduced lung bacterial loads of rats infected with the penicillin-susceptible strain. Against the penicillin-resistant strain, teicoplanin displayed a significant activity regardless of the immununological status of the animals. Penicillin G significantly reduced lung bacterial load of the penicillin-resistant strain only in immunocompetent rats and at a higher dose than needed in treatment of the penicillin-susceptible infection. The experimental models described here could be suitable for studying the efficacy of antibacterial agents against pulmonary infections caused by penicillin-susceptible and penicillin-resistant S. pneumoniae strains.

Animals↗

PubMed2001

Study on the pathophysiology of experimental Burkholderia pseudomallei infection in mice.

Burkholderia pseudomallei is the etiological agent of melioidosis, a potentially fatal disease occurring in man and animals. The aim of this study was to investigate the pathophysiological course of experimental melioidosis, and to identify the target organs, in an animal model. For this purpose SWISS mice were infected intraperitoneally with the virulent strain B. pseudomallei 6068. The bacterial load of various organs was quantified daily by bacteriological analysis and by an enzyme-linked immunosorbent assay (ELISA) based on a monoclonal antibody specific to B. pseudomallei exopolysaccharide (EPS). Electron microscopic investigation of the spleen was performed to locate the bacteria at the cellular level. In this model of acute melioidosis, B. pseudomallei had a marked organ tropism for liver and spleen, and showed evidence of in vivo growth with a bacterial burden of 1.6x10(9) colony forming units (CFU) per gram of spleen 5 days after infection with 200 CFU. The highest bacterial loads were detected in the spleen at all time points, in a range from 2x10(6) to 2x10(9) CFU g(-1). They were still 50-80 times greater than the load of the liver at the time of peak burden. Other investigated organs such as lungs, kidneys, and bone marrow were 10(2)-10(4)-fold less infected than the spleen, with loads ranging from 3x10(2) to 3x10(6) CFU g(-1). The heart and the brain were sites of a delayed infection, with counts in a range from 10(3) to 10(7) times lower than bacterial counts in the spleen. The EPS-specific ELISA proved to be highly sensitive, particularly at the level of those tissues in which colony counting on agar revealed low contamination. In the blood, EPS was detected at concentrations corresponding to bacterial loads ranging from 8x10(3) to 6x10(4) CFU ml(-1). Electron microscopic examination of the spleen revealed figures of phagocytosis, and the presence of large numbers of intact bacteria, which occurred either as single cells or densely packed into vacuoles. Sparse figures suggesting bacterial replication were also observed. In addition, some bacteria could be seen in vacuoles that seemed to have lost their membrane. These observations provide a basis for further investigations on the pathogenesis of the disease.

Animals↗

PubMed2006

Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD.

STUDY OBJECTIVES: The inflammatory responses and associated clinical severity of COPD exacerbations are greatly variable, and the determinants of these factors are poorly understood. We examined the hypothesis that bacteria and viruses may modulate this heterogeneity and that interactions between bacterial and viral infection may affect changes in airway bacterial load and the clinical features and inflammatory responses of exacerbations in patients with COPD. DESIGN: Prospective cohort study. SETTING: Outpatient Department, London Chest Hospital, London, UK. PATIENTS: Thirty-nine patients with COPD. MEASUREMENTS: We prospectively studied 56 COPD exacerbations, obtaining clinical data and paired sputum and serum samples at baseline and exacerbation. Qualitative and quantitative microbiology, polymerase chain reaction detection for rhinovirus, and estimation of cytokine levels by enzyme-linked immunosorbent assay were performed. RESULTS: A total of 69.6% of exacerbations were associated with a bacterial pathogen, most commonly Haemophilus influenzae. Rhinovirus was identified in 19.6% of exacerbations. The rise in bacterial load at exacerbation correlated with the rise in sputum interleukin (IL)-8 (r = 0.37, p = 0.022) and fall in FEV1 (r = 0.35, p = 0.048). Exacerbations with both rhinovirus and H. influenzae had higher bacterial loads (10(8.56) cfu/mL vs 10(8.05)cfu/mL, p = 0.018) and serum IL-6 (13.75 pg/mL vs 6.29 pg/mL, p = 0.028) than exacerbations without both pathogens. In exacerbations with both cold symptoms (a marker of putative viral infection) and a bacterial pathogen, the FEV1 fall was greater (20.3% vs 3.6%, p = 0.026) and symptom count was higher (p = 0.019) than those with a bacterial pathogen alone. CONCLUSIONS: The clinical severity and inflammatory responses in COPD exacerbations are modulated by the nature of the infecting organism: bacterial and viral pathogens interact to cause additional rises in inflammatory markers and greater exacerbation severity.

Aged↗

PubMed2003

Nitric oxide partially controls Coxiella burnetii phase II infection in mouse primary macrophages.

In most primary or continuous cell cultures infected with the Q-fever agent Coxiella burnetii, bacteria are typically sheltered in phagolysosome-like, large replicative vacuoles (LRVs). We recently reported that only a small proportion of mouse peritoneal macrophages (PMPhi) infected with a nonvirulent, phase II strain of C. burnetii developed LRVs and that their relative bacterial load increased only slowly. In the majority of infected PMPhi, the bacteria were confined to the small vesicles. We show here that nitric oxide (NO) induced by the bacteria partially accounts for the restricted development of LRVs in primary macrophages. Thus, (i) PMPhi and bone marrow-derived macrophages (BMMPhi) challenged with phase II C. burnetii produced significant amounts of NO; (ii) the NO synthase inhibitors aminoguanidine and N-methyl-L-arginine reduced the production of NO and increased the frequency of LRVs (although the relative bacterial loads of individual LRVs did not change, the estimated loads per well increased appreciably); (iii) gamma interferon (IFN-gamma) or the NO donor sodium nitroprusside, added to BMMPhi prior to or after infection, reduced the development and the relative bacterial loads of LRVs and lowered the yield of viable bacteria recovered from the cultures; and (iv) these effects of IFN-gamma may not be entirely dependent on the production of NO since IFN-gamma also controlled the infection in macrophages from inducible NO synthase knockout mice. It remains to be determined whether NO reduced the development of LRVs by acting directly on the bacteria; by acting on the traffic, fusion, or fission of cell vesicles; or by a combination of these mechanisms.

Animals↗

PubMed2006

Efficacy and potential for resistance selection of antipseudomonal treatments in a mouse model of lung infection by hypermutable Pseudomonas aeruginosa.

Hypermutable Pseudomonas aeruginosa strains are found with high frequency in the lungs of patients with chronic infections and are associated with high antibiotic resistance rates. The in vivo consequences of hypermutation for treatment in a mouse model of lung infection using strain PAO1 and its hypermutable derivative PAOdeltamutS are investigated. Groups of 30 mice were treated for 3 days with humanized regimens of ciprofloxacin (CIP), tobramycin (TOB), CIP plus TOB, or placebo, and mortality, total lung bacterial load, and 4x- and 16x-MIC mutants were recorded. The rates of mutation and the initial in vivo frequencies of mutants (at the onset of treatment) were also estimated and the in vitro- and in vivo-selected mutants characterized. Since both strains had identical MICs, the same pharmacokinetic/pharmacodynamic (PK/PD) parameters were obtained: area under the 24-h concentration-time curve (fAUC)/MIC = 385 for CIP and maximum concentration of drug in serum (fC(max))/MIC = 19 for TOB. Despite adequate PK/PD parameters, persistence of high bacterial numbers and amplification (50,000-fold) of resistant mutants (MexCD-OprJ hyperexpression) were documented with CIP treatment for PAOdeltamutS, in contrast to complete resistance suppression for PAO1 (P < 0.01), showing that conventional PK/PD parameters may not be applicable to infections by hypermutable strains. On the other hand, the efficacy of TOB monotherapy in terms of mortality reduction and bacterial load was very low regardless of the strain but not due to resistance development, since mutants were not selected for PAO1 and were only modestly amplified for PAOdeltamutS. Finally, the CIP-plus-TOB combination was synergistic, further reducing mortality and bacterial load and completely preventing resistance even for PAOdeltamutS (P < 0.01 compared to monotherapy), showing that it is possible to suppress resistance selection in infections by hypermutable P. aeruginosa using appropriate combined regimens.

Animals↗