Evaluation of azlocillin in-vitro and in discriminative animal models of infection

Azlocillin was more active in vitro than ticarcillin or carbenicillin against 561 aminoglycoside-resistant strains of Pseudomonas aeruginosa collected from 74 hospitals distributed over a wide geographic area in the eastern United States. Azlocillin was compared with various other antimicrobial agents in discriminative animal models of Ps. aeruginosa pyelonephritis, osteomyelitis, endocarditis, and meningitis in a variety of mammalian species. Cefsulodin was more effective than azlocillin in reducing Ps. aeruginosa kidney concentrations in rat pyelonephritis induced by intrarenal inoculation. The mean±s.d. logl0 cfu/g kidney after three days of therapy were as follows: controls = 5.4±1.5, azlocillin = 4.4±1.8, cefsulodin = 2.6±0.9 (P < 0.01) but the MBC for the test strain was eight-fold higher for azlocillin (8 vs. 1 mg/l) and effective concentrations were maintained longer in rat serum for cefsulodin as against azlocillin. In addition, ticarcillin reduced kidney bacterial concentrations faster than azlocillin in a mouse pyelonephritis model induced by intravenous Ps. aeruginosa inoculation with subsequent iron loading. Azlocillin was less effective than tobramycin in experimental chronic Ps. aeruginosa osteomyelitis induced in rabbits by direct injection into the tibia. An azlocillin-tobramycin regimen was not more effective than tobramycin alone. After 28 days of therapy, the percentages of positive bone cultures after death were as follows: no antibiotic (controls) = 92%, azlocillin = 95%, tobramycin = 76%, azlocillin plus tobramycin = 60%. Both ticarcillin and azlocillin were less active than tobramycin in experimental Ps. aeruginosa endocarditis induced in rabbits by intravenous inoculation of 108 cfu following 1 h of catheter induced aortic valve trauma. The best results were noted with an azlocillin-tobramycin regimen. The mean±s.d. log10 cfu Ps. aeruginosa/g vegetation after five days of therapy were as follows: no antibiotic controls = 8.1 ± 1.1, tobramycin = 4.5 ±0.8, ticarcillin = 6.9 ± 0.8, azlocillin = 5.7 ± 1.5, ticarcillin phis tobramycin = 4.9 ± 1.0, azlocillin plus tobramycin = 3.3 ± 1.6. Sterile vegetations were rarely attained with any regimen. The mean percentage penetration into purulent cerebrospinal fluid (CSF) in experimental Ps. aeruginosa meningitis for azlocillin was 13.3%, comparable to many other β-lactam antibiotics. Azlocillin was the single most active (P < 0.01) agent evaluated after 8 h intravenous infusions in this model. An azlocillin-amikacin regimen was more rapidly bactericidal (P < 0.01) than either agent alone in vivo. None of the agents evaluated alone or in combination, however, produced a sterile CSF after 8 h of therapy in any anima

The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens

Zinc (Zn) and copper (Cu) are essential for optimal innate immune function, and nutritional deficiency in either metal leads to increased susceptibility to bacterial infection. Recently, the decreased survival of bacterial pathogens with impaired Cu and/or Zn detoxification systems in phagocytes and animal models of infection has been reported. Consequently, a model has emerged in which the host utilizes Cu and/or Zn intoxication to reduce the intracellular survival of pathogens. This review describes and assesses the potential role for Cu and Zn intoxication in innate immune function and their direct bactericidal function

Molecular biology and pathogenesis of hepatitis E virus

The hepatitis E virus (HEV) is a small RNA virus and the etiological agent for hepatitis E, a form of acute viral hepatitis. The virus has a feco-oral transmission cycle and is transmitted through environmental contamination, mainly through drinking water. Recent studies on the isolation of HEV-like viruses from animal species also suggest zoonotic transfer of the virus. The absence of small animal models of infection and efficient cell culture systems has precluded virological studies on the replication cycle and pathogenesis of HEV. A vaccine against HEV has undergone successful clinical testing and diagnostic tests are available. This review describes HEV epidemiology, clinical presentation, pathogenesis, molecular virology and the host response to HEV infection. The focus is on published literature in the past decade

Antiviral Activity of 4′-thioIDU and Thymidine Analogs against Orthopoxviruses

The search for effective therapies for orthopoxvirus infections has identified diverse classes of molecules with antiviral activity. Pyrimidine analogs, such as 5-iodo-2′-deoxyuridine (idoxuridine, IDU) were among the first compounds identified with antiviral activity against a number of orthopoxviruses and have been reported to be active both in vitro and in animal models of infection. More recently, additional analogs have been reported to have improved antiviral activity against orthopoxviruses including several derivatives of deoxyuridine with large substituents in the 5 position, as well as analogs with modifications in the deoxyribose moiety including (north)-methanocarbathymidine, and 5-iodo-4′-thio-2′-deoxyuridine (4′-thioIDU). The latter molecule has proven to have good antiviral activity against the orthopoxviruses both in vitro and in vivo and has the potential to be an effective therapy in humans

Lack of Evidence for the Direct Activation of Endothelial Cells by Adult Female and Microfilarial Excretory-Secretory Products

Lymphangiectasia (dilation of the lymphatic vessel (LV)) is pathognomonic for lymphatic filariasis. In both infected humans and animal models of infection, lymphangiectasia is not restricted to the site of the worm nest, but is found along the infected vessel. These observations argue that soluble products secreted by the worm could be mediating this effect by activating the lymphatic endothelial cells (LEC) lining the vessel. We tested the ability of filarial Excretory-Secretory products to activate LECs, but were unable to detect a direct effect of the Excretory-Secretory products on the activation of LEC as assessed by a variety of approaches including cellular proliferation, cell surface molecule expression and cytokine and growth factor production (although other mediators used as positive controls did induce these effects). Collectively, these results do not support the hypothesis that Excretory-Secretory products directly activate LECs

Experimental methods to study the pathogenesis of human enteric RNA viruses

Every year, millions of children are infected with viruses that target the gastrointestinal tract, causing acute gastroenteritis and diarrheal illness. Indeed, approximately 700 million episodes of diarrhea occur in children under five annually, with RNA viruses norovirus, rotavirus, and astrovirus serving as major causative pathogens. Numerous methodological advancements in recent years, including the establishment of novel cultivation systems using enteroids as well as the development of murine and other animal models of infection, have helped provide insight into many features of viral pathogenesis. However, many aspects of enteric viral infections remain elusive, demanding further study. Here, we describe the different in vitro and in vivo tools available to explore different pathophysiological attributes of human enteric RNA viruses, highlighting their advantages and limitations depending upon the question being explored. In addition, we discuss key areas and opportunities that would benefit from further methodological progress

Titration of C-5 Sterol Desaturase Activity Reveals Its Relationship to Candida albicans Virulence and Antifungal Susceptibility Is Dependent upon Host Immune Status

Mutations that completely inactivate Erg3p enable the prevalent human pathogen C. albicans to endure the azole antifungals in vitro . However, such null mutants are less frequently identified in azole-resistant clinical isolates than other resistance mechanisms, and previous studies have reported conflicting outcomes regarding antifungal resistance of these mutants in animal models of infection

Maternal Filovirus Infection and Death from Marburg and Ravn Viruses: Highly Lethal to Pregnant Women and Their Fetuses Similar to Ebola Virus

Ebola virus and the marburgviruses are distinct filoviruses that share common clinical presentations and clinical management protocols. However, the marburgviruses are not as well known as is their close relative, Ebola virus, and are a much less frequent cause of human outbreaks. Marburg virus disease (MVD) is caused by two marburgviruses that are clinically indistinguishable—Marburg virus and Ravn virus. There is scant information available concerning MVD in pregnancy, but it appears clear that, similar to Ebola virus, MVD infection is associated with an extremely high maternal and fetal mortality rate. This chapter will examine what is known about Marburg and Ravn virus infections in pregnant women, their clinical outcomes, and the pathogenesis of MVD in experimental animal models of infection. These data will be compared with the more comprehensive information available regarding Ebola virus disease in pregnancy including its effects on pregnant women and the fetus