scholarly journals Efficacy of SCH27899 in an Animal Model of Legionnaires' Disease Using Immunocompromised A/J Mice

2000 ◽  
Vol 44 (5) ◽  
pp. 1333-1336 ◽  
Author(s):  
Joan K. Brieland ◽  
David Loebenberg ◽  
Fred Menzel ◽  
Roberta S. Hare
Keyword(s):  
Animal Model ◽  
Murine Model ◽  
Legionella Pneumophila ◽  
Immunocompromised Host ◽  
Lung Infection ◽  
Cortisone Acetate ◽  
Contrast Administration ◽  
Once Daily ◽  
Legionnaires Disease ◽  
Lung Infections

ABSTRACT The efficacy of SCH27899, a new everninomicin antibiotic, against replicative Legionella pneumophila lung infections in an immunocompromised host was evaluated using a murine model of Legionnaires' disease. A/J mice were immunocompromised with cortisone acetate and inoculated intratracheally with L. pneumophilaserogroup 1 (105 CFU per mouse). At 24 h postinoculation, mice were administered either SCH27899 (6 to 60 mg/kg [MPK] intravenously) or a placebo once daily for 5 days, and mortality and intrapulmonary growth of L. pneumophila were assessed. In the absence of SCH27899, there was 100% mortality inL. pneumophila-infected mice, with exponential intrapulmonary growth of the bacteria. In contrast, administration of SCH27899 at a dose of ≥30 MPK resulted in ≥90% survival of infected mice, which was associated with inhibition of intrapulmonary growth ofL. pneumophila. In subsequent studies, the efficacy of SCH27899 was compared to ofloxacin (OFX) and azithromycin (AZI). Administration of SCH27899, OFX, or AZI at a dose of ≥30 MPK once daily for 5 days resulted in ≥85% survival of infected mice and inhibition of intrapulmonary growth of the bacteria. However, L. pneumophila CFU were recovered in lung homogenates following cessation of therapy with all three antibiotics. These studies demonstrate that SCH27899 effectively prevents fatal replicativeL. pneumophila lung infection in immunocompromised A/J mice by inhibition of intrapulmonary growth of the bacteria. However, in this murine model of pulmonary legionellosis, SCH27899, like OFX and AZI, was bacteriostatic.

scholarly journals Activities of Tigecycline (GAR-936) against Legionella pneumophila In Vitro and in Guinea Pigs with L. pneumophila Pneumonia

2003 ◽  
Vol 47 (2) ◽  
pp. 533-540 ◽  
Author(s):  
Paul H. Edelstein ◽  
William J. Weiss ◽  
Martha A. C. Edelstein
Keyword(s):  
Guinea Pig ◽  
Legionella Pneumophila ◽  
Guinea Pigs ◽  
Time Curve ◽  
Once Daily ◽  
Susceptibility Data ◽  
Days Of Therapy ◽  
Dosing Regimens ◽  
Legionnaires Disease

ABSTRACT The activities of tigecycline (Wyeth Research) against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia were studied. The tigecycline MIC at which 50% of strains are inhibited for 101 different Legionella sp. strains was 4 μg/ml versus 0.125 and 0.25 μg/ml for azithromycin and erythromycin, respectively. Tigecycline was about as active as erythromycin (tested at 1 μg/ml) against the F889 strain of L. pneumophila grown in guinea pig alveolar macrophages and more active than erythromycin against the F2111 strain. Azithromycin (0.25 μg/ml) was more active than (F889) or as active as (F2111) tigecycline (1 μg/ml) in the macrophage model. When tigecycline was given (7.5 mg/kg of body weight subcutaneously once) to guinea pigs with L. pneumophila pneumonia, the mean peak serum and lung levels were 2.3 and 1.8 μg/ml (1.2 and 1.5 μg/g) at 1 and 2 h postinjection, respectively. The serum and lung areas under the concentration time curve from 0 to 24 h were 13.7 and 15.8 μg · h/ml, respectively. Thirteen of 16 guinea pigs with L. pneumophila pneumonia treated with tigecycline (7.5 mg/kg subcutaneously once daily for 5 days) survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin (15 mg/kg intraperitoneally once daily for 2 days). None of 12 guinea pigs treated with saline survived. Tigecycline-treated guinea pigs had average end of therapy lung counts of 1 × 106 CFU/g (range, 2.5 × 104 to 3.2 × 106 CFU/g) versus <1 × 102 CFU/g for azithromycin (range, undetectable to 100 CFU/g). A second guinea pig study examined the ability of tigecycline to clear L. pneumophila from the lung after 5 to 9 days of therapy; bacterial concentrations 1 day posttherapy ranged from log10 4.2 to log10 5.5 CFU/g for four different dosing regimens. Tigecycline is about as effective as erythromycin against intracellular L. pneumophila, but tigecycline inactivation by the test media confounded the interpretation of susceptibility data. Tigecycline was effective at preventing death from pneumonia in an animal model of Legionnaires' disease, warranting human clinical trials of the drug for the disease.

scholarly journals Immunomodulatory Role of Endogenous Interleukin-18 in Gamma Interferon-Mediated Resolution of Replicative Legionella pneumophila Lung Infection

2000 ◽  
Vol 68 (12) ◽  
pp. 6567-6573 ◽  
Author(s):  
Joan K. Brieland ◽  
Craig Jackson ◽  
Steve Hurst ◽  
David Loebenberg ◽  
Tony Muchamuel ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Lavage Fluid ◽  
Lung Infection ◽  
Gamma Interferon ◽  
Pcr Analysis ◽  
Interleukin 18 ◽  
Legionnaires Disease ◽  
Ifn Γ

ABSTRACT The in vivo role of endogenous interleukin-18 (IL-18) in modulating gamma interferon (IFN-γ)-mediated resolution of replicativeLegionella pneumophila lung infection was assessed using a murine model of Legionnaires' disease. Intratracheal inoculation of A/J mice with virulent bacteria (106 L. pneumophila organisms per mouse) resulted in induction of IL-18 protein in bronchoalveolar lavage fluid (BALF) and intrapulmonary expression of IL-18 mRNA. Real-time quantitative RT-PCR analysis of infected lung tissue demonstrated that induction of IL-18 in BALF preceded induction of IL-12 and IFN-γ mRNAs in the lung. Blocking intrapulmonary IL-18 activity by administration of a monoclonal antibody (MAb) to the IL-18 receptor (anti-IL-18R MAb) prior toL. pneumophila infection inhibited induction of intrapulmonary IFN-γ production but did not significantly alter resolution of replicative L. pneumophila lung infection. In contrast, blocking endogenous IL-12 activity by administration of anti-IL-12 MAb) alone or in combination with anti-IL-18R MAb inhibited induction of intrapulmonary IFN-γ and resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection. Taken together, these results demonstrate that IL-18 plays a key role in modulating induction of IFN-γ in the lung in response to L. pneumophila and that together with IL-12, IL-18 regulates intrapulmonary growth of the bacteria.

scholarly journals In Vitro Activity of Gemifloxacin (SB-265805, LB20304a) against Legionella pneumophila and Its Pharmacokinetics in Guinea Pigs with L. pneumophila Pneumonia

2001 ◽  
Vol 45 (8) ◽  
pp. 2204-2209 ◽  
Author(s):  
Paul H. Edelstein ◽  
Takashi Shinzato ◽  
Edward Doyle ◽  
Martha A. C. Edelstein
Keyword(s):  
Guinea Pig ◽  
Legionella Pneumophila ◽  
Half Life ◽  
Guinea Pigs ◽  
Clinical Effectiveness ◽  
Drug Dose ◽  
Time Curve ◽  
Once Daily ◽  
Legionnaires Disease

ABSTRACT The activity of gemifloxacin against intracellularLegionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia was studied. Gemifloxacin, azithromycin, and levofloxacin (1 μg/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 2 to 3 log10 units. Gemifloxacin and levofloxacin had roughly equivalent intracellular activities. In contrast, erythromycin had static activity only. Therapy studies of gemifloxacin, azithromycin, and levofloxacin were performed in guinea pigs with L. pneumophila pneumonia. When gemifloxacin (10 mg/kg) was given by the intraperitoneal (i.p.) route to infected guinea pigs, mean peak levels in plasma were 1.3 μg/ml at 0.5 h and 1.2 μg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 1.3 h, and the area under the concentration-time curve from 0 to 24 h (AUC0–24) was 2.1 μg · h/ml. For the same drug dose, mean levels in lungs were 3.4 μg/g at both 0.5 and 1 h, with a half-life of 1.5 h and an AUC0–24 of 6.0 μg · h/ml. All 15 L. pneumophila-infected guinea pigs treated with gemifloxacin (10 mg/kg/dose given i.p. once daily) for 2 days survived for 9 days after antimicrobial therapy, as did 13 of 14 guinea pigs treated with the same dose of gemifloxacin given for 5 days. All 12 azithromycin-treated animals (15 mg/kg/dose given i.p. once daily for 2 days) survived, as did 11 of 12 animals treated with levofloxacin (10 mg/kg/dose given i.p. once daily for 5 days). None of 12 animals treated with saline survived. Gemifloxacin is effective against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease, even with an abbreviated course of therapy. These data support studies of the clinical effectiveness of gemifloxacin for the treatment of Legionnaires' disease.

scholarly journals Acute Pneumonia Caused by Clinically Isolated Legionella pneumophila Sg 1, ST 62: Host Responses and Pathologies in Mice

2022 ◽  
Vol 10 (1) ◽  
pp. 179
Author(s):  
Jiří Trousil ◽  
Lucia Frgelecová ◽  
Pavla Kubíčková ◽  
Kristína Řeháková ◽  
Vladimír Drašar ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Lung Infection ◽  
Severe Form ◽  
Host Immunity ◽  
Sequence Type ◽  
Host Responses ◽  
Lung Pathology ◽  
Bacterial Clearance ◽  
Acute Pneumonia ◽  
Legionnaires Disease

Legionnaires’ disease is a severe form of lung infection caused by bacteria belonging to the genus Legionella. The disease severity depends on both host immunity and L. pneumophila virulence. The objective of this study was to describe the pathological spectrum of acute pneumonia caused by a virulent clinical isolate of L. pneumophila serogroup 1, sequence type 62. In A/JOlaHsd mice, we compared two infectious doses, namely, 104 and 106 CFU, and their impact on the mouse status, bacterial clearance, lung pathology, and blood count parameters was studied. Acute pneumonia resembling Legionnaires’ disease has been described in detail.

scholarly journals The Burkholderia cenocepacia Type VI Secretion System Effector TecA Is a Virulence Factor in Mouse Models of Lung Infection

mBio ◽  
2021 ◽  
Author(s):  
Nicole A. Loeven ◽  
Andrew I. Perault ◽  
Peggy A. Cotter ◽  
Craig A. Hodges ◽  
Joseph D. Schwartzman ◽  
...  
Keyword(s):  
Animal Model ◽  
Mouse Models ◽  
Close Association ◽  
Lung Infection ◽  
Secretion System ◽  
Burkholderia Cenocepacia ◽  
Type Vi Secretion System ◽  
Content Type ◽  
Type Vi Secretion ◽  
Lung Infections

B. cenocepacia is often considered the most virulent species in the Bcc because of its close association with cepacia syndrome in addition to its capacity to cause chronic lung infections in CF patients (1). Prior to the current study, virulence factors of B. cenocepacia important for causing lethal disease had not been identified in a CF animal model of lung infection.

scholarly journals In Vitro Activity of the Ketolide HMR 3647 (RU 6647) for Legionella spp., Its Pharmacokinetics in Guinea Pigs, and Use of the Drug To Treat Guinea Pigs withLegionella pneumophila Pneumonia

1999 ◽  
Vol 43 (1) ◽  
pp. 90-95 ◽  
Author(s):  
Paul H. Edelstein ◽  
Martha A. C. Edelstein
Keyword(s):  
Guinea Pig ◽  
Alveolar Macrophages ◽  
Legionella Pneumophila ◽  
Guinea Pigs ◽  
Peak Plasma ◽  
Once Daily ◽  
Legionnaires Disease ◽  
Guinea Pig Model ◽  
Therapy Studies

ABSTRACT The activities of HMR 3647, HMR 3004, erythromycin, clarithromycin, and levofloxacin for 97 Legionella spp. isolates were determined by microbroth dilution susceptibility testing. Growth inhibition of two Legionella pneumophila strains grown in guinea pig alveolar macrophages was also determined. The concentrations required to inhibit 50% of strains tested were 0.06, 0.02, 0.25, 0.03, and 0.02 μg/ml for HMR 3647, HMR 3004, erythromycin, clarithromycin, and levofloxacin, respectively. BYEα broth did not significantly inhibit the activities of the drugs tested, as judged by the susceptibility of the control Staphylococcus aureus strain; however, when Escherichia coli was used as the test strain, levofloxacin activity tested in BYEα broth was fourfold lower. HMR 3647, HMR 3004, erythromycin, and clarithromycin (0.25 and 1 μg/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 0.5 to 1 log10, but regrowth occurred over a 2-day period. HMR 3647, erythromycin, and clarithromycin appeared to have equivalent intracellular activities which were solely static in nature. HMR 3004 was more active than all drugs tested except levofloxacin. In contrast, levofloxacin (1 μg/ml) was bactericidal against intracellular L. pneumophilaand significantly more active than the other drugs tested. Therapy studies with HMR 3647 and erythromycin were performed in guinea pigs with L. pneumophila pneumonia. When HMR 3647 was given (10 mg/kg of body weight) by the intraperitoneal route to infected guinea pigs, mean peak plasma levels were 1.4 μg/ml at 0.5 h and 1.0 μg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 1.4 h. All 16 L. pneumophila-infected guinea pigs treated with HMR 3647 (10 mg/kg/dose given intraperitoneally once daily) for 5 days survived for 9 days after antimicrobial therapy, as did all 16 guinea pigs treated with the same dose of HMR 3647 given twice daily. Fourteen of 16 erythromycin-treated (30 mg/kg/dose given intraperitoneally twice daily) animals survived, whereas 0 of 12 animals treated with saline survived. HMR 3647 is effective against L. pneumophilain vitro, in infected macrophages, and in a guinea pig model of Legionnaires’ disease. HMR 3647 given once daily should be evaluated as a treatment for Legionnaires’ disease in humans.

Subtyping ofLegionella pneumophilaisolates by arbitrarily primed polymerase chain reaction

1995 ◽  
Vol 41 (9) ◽  
pp. 846-848 ◽  
Author(s):  
E. Ledesma ◽  
J. Llorca ◽  
M. A. Dasí ◽  
M. L. Camaró ◽  
E. Carbonell ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Legionella Pneumophila ◽  
Water Sources ◽  
Chain Reaction ◽  
Single Room ◽  
Legionnaires Disease ◽  
Polymerase Chain ◽  
Resort Hotel ◽  
Different Water Sources

Arbitrarily primed polymerase chain reaction (AP-PCR) was used to differentiate strains of Legionella pneumophila isolated from different water sources in a resort hotel in Benidorm, Alicante, Spain, where an outbreak of Legionnaires' disease occurred among a group of tourists between 65 and 80 years of age. All isolates were L. pneumophila serogroup 1, subtype Pontiac (Knoxville 1). Five different patterns (P1 to P5) were obtained by AP-PCR. The number of bands per pattern varied between 4 and 11. Patterns P1 and P2 represented 60 and 20% of L. pneumophila isolates, respectively. Since different subpopulations of L. pneumophila coexisted (up to three different AP-PCR patterns were identified in a single room), it was not possible to link an individual L. pneumophila strain to the occurrence of this outbreak.Key words: Legionella pneumophila, AP-PCR, subtyping, outbreak.

scholarly journals Human Lung Tissue Explants Reveal Novel Interactions during Legionella pneumophila Infections

2013 ◽  
Vol 82 (1) ◽  
pp. 275-285 ◽  
Author(s):  
Jens Jäger ◽  
Sebastian Marwitz ◽  
Jana Tiefenau ◽  
Janine Rasch ◽  
Olga Shevchuk ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Legionella Pneumophila ◽  
Human Lung ◽  
Transcriptional Response ◽  
Human Infection ◽  
Bacterial Invasion ◽  
Human Lung Tissue ◽  
Content Type ◽  
Tissue Explants ◽  
Legionnaires Disease

ABSTRACTHistological and clinical investigations describe late stages of Legionnaires' disease but cannot characterize early events of human infection. Cellular or rodent infection models lack the complexity of tissue or have nonhuman backgrounds. Therefore, we developed and applied a novel model forLegionella pneumophilainfection comprising living human lung tissue. We stimulated lung explants withL. pneumophilastrains and outer membrane vesicles (OMVs) to analyze tissue damage, bacterial replication, and localization as well as the transcriptional response of infected tissue. Interestingly, we found that extracellular adhesion ofL. pneumophilato the entire alveolar lining precedes bacterial invasion and replication in recruited macrophages. In contrast, OMVs predominantly bound to alveolar macrophages. Specific damage to septa and epithelia increased over 48 h and was stronger in wild-type-infected and OMV-treated samples than in samples infected with the replication-deficient, type IVB secretion-deficient DotA−strain. Transcriptome analysis of lung tissue explants revealed a differential regulation of 2,499 genes after infection. The transcriptional response included the upregulation of uteroglobin and the downregulation of the macrophage receptor with collagenous structure (MARCO). Immunohistochemistry confirmed the downregulation of MARCO at sites of pathogen-induced tissue destruction. Neither host factor has ever been described in the context ofL. pneumophilainfections. This work demonstrates that the tissue explant model reproduces realistic features of Legionnaires' disease and reveals new functions for bacterial OMVs during infection. Our model allows us to characterize early steps of human infection which otherwise are not feasible for investigations.

How the parasitic bacterium Legionella pneumophila modifies its phagosome and transforms it into rough ER: implications for conversion of plasma membrane to the ER membrane

2001 ◽  
Vol 114 (24) ◽  
pp. 4637-4650 ◽  
Author(s):  
Lewis G. Tilney ◽  
Omar S. Harb ◽  
Patricia S. Connelly ◽  
Camenzind G. Robinson ◽  
Craig R. Roy
Keyword(s):  
Legionella Pneumophila ◽  
Mitochondrial Membranes ◽  
Macrophage Infection ◽  
Thin Sections ◽  
Stage Process ◽  
Legionnaires Disease ◽  
Rough Er ◽  
Membrane Changes ◽  
Phagosomal Membrane

Within five minutes of macrophage infection by Legionella pneumophila, the bacterium responsible for Legionnaires’ disease, elements of the rough endoplasmic reticulum (RER) and mitochondria attach to the surface of the bacteria-enclosed phagosome. Connecting these abutting membranes are tiny hairs, which are frequently periodic like the rungs of a ladder. These connections are stable and of high affinity - phagosomes from infected macrophages remain connected to the ER and mitochondria (as they were in situ) even after infected macrophages are homogenized. Thin sections through the plasma and phagosomal membranes show that the phagosomal membrane is thicker (72±2 Å) than the ER and mitochondrial membranes (60±2 Å), presumably owing to the lack of cholesterol, sphingolipids and glycolipids in the ER. Interestingly, within 15 minutes of infection, the phagosomal membrane changes thickness to resemble that of the attached ER vesicles. Only later (e.g. after six hours) does the ER-phagosome association become less frequent. Instead ribosomes stud the former phagosomal membrane and L. pneumophila reside directly in the rough ER. Examination of phagosomes of various L. pneumophila mutants suggests that this membrane conversion is a four-stage process used by L. pneumophila to establish itself in the RER and to survive intracellularly. But what is particularly interesting is that L. pneumophila is exploiting a poorly characterized naturally occuring cellular process.

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