Aminophylline-induced suppression of pulmonary antibacterial defenses

Respiratory infections are frequently observed in patients with chronic obstructive pulmonary disease, indicating that host defenses are compromised. Antibacterial defenses of the lung against such infections include the alveolar macrophage and polymorphonuclear leukocytes (PMN) that migrate into the lung to provide auxiliary phagocytic defenses. To test the hypothesis that aminophylline acutely impairs pulmonary antibacterial defenses, mice were challenged by aerosol inhalation with Staphylococcus aureus or Proteus mirabilis and injected intraperitoneally with aminophylline (20, 40, or 80 mg/kg). Pulmonary bactericidal activity and total lavaged lung cell and differential counts were determined 4 h after bacterial challenge. The highest dose of aminophylline suppressed the killing of S. aureus so that 55 +/- 5% of the initial viable bacteria remained as compared with 22 +/- 4% in the control animals. In contrast, there was a dose-related suppression of pulmonary antibacterial defenses against gram-negative bacteria. With doses of 40 and 80 mg/kg, lung defenses were ablated, allowing the proliferation of P. mirabilis to 115 +/- 9% and 253 +/- 9%, respectively, the control value being 26 +/- 3%. The number of PMN obtained by lavage after aerosol challenge with P. mirabilis was also inhibited by aminophylline in a dose-dependent manner. From the lungs of untreated animals 5.0 +/- 0.3 X 10(6) PMN were recovered as compared with 3.3 +/- 0.1 X 10(6), 2.5 +/- 0.2 X 10(6), and 1.8 +/- 0.1 X 10(6), respectively, with increasing doses of aminophylline. The bactericidal activity of lavaged PMN from the lungs of aminophylline-treated rats challenged with the gram-negative bacterium in vivo was significantly depressed when compared with that in control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrapulmonary pharmacokinetics of antibacterial agents: implications for therapeutics

The idea of studying the pharmacokinetics and pharmacodynamics of antibacterials in order to predict their efficacy has long been of interest. Traditionally, serum drug concentrations have been evaluated against the minimum inhibitory concentration (MIC) of a given pathogen; however, infection site-specific data continue to gain interest from clinicians. Despite methodological limitations, progress in techniques has improved the clinical significance of data generated. Rather than using tissue homogenates which fail to differentiate between interstitial and intracellular concentrations, newer collection techniques focus on sampling of matrices that allow for this differentiation. These collection techniques now allow one to accurately describe beta-lactam and aminoglycoside interstitial penetrations, as well as, the interstitial and phagocytic concentrations of macrolides and fluoroquinolones. By using these specific data and the MICs of infecting pathogens, it is hoped that conclusions can be drawn by a clinician as to the appropriateness of the choice of an antibacterial.     

Endotoxin-induced suppression of pulmonary antibacterial defenses against Staphylococcus aureus

In order to evaluate the effect of endotoxin on lung host defenses, Sprague-Dawley rats were intravenously injected with either placebo or 5 mg/kg of Escherichia coli lipopolysaccharide B. Two hours after treatment, animals were challenged with Staphylococcus aureus by either low dose aerosol inhalation or high dose intratracheal instillation of the bacteria into the lungs. Quantitative lung bacteriologic examination and bronchoalveolar lavage (BAL) for total and differential cell counts were performed immediately (zero hour) and at 4 h after bacterial challenge. Lung phagocytic defenses against aerosolized S. aureus challenges are provided solely by the alveolar macrophage (AM) in the absence of inflammation. In aerosol-challenged control rats, 20.6 +/- 2.0% of the initial deposited bacterial challenge remained viable in the lung at 4 h. Animals pretreated with endotoxin, however, showed a significant decrease in pulmonary bactericidal activity (31.3 +/- 3.4% bacteria remaining at 4 h), indicating a defect in alveolar macrophage (AM) function. Further assessment of the bactericidal oxidative metabolism of endotoxin-treated AM by luminol-enhanced chemiluminescence indicated an increased production of free radical oxygen species when compared with control nontreated cells in both the unstimulated (66 +/- 4 versus 38 +/- 7 x 10(3) cpm in control) and stimulated (250.5 +/- 17.1 versus 147.1 +/- 6.2 x 10(3) cpm in control) states. Total and differential cell counts in both control and endotoxin-treated aerosol-challenged rats were similar.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of common sclerosing agents on the rabbit pleural space

New Zealand white rabbits received intrapleural instillations of either tetracycline (7, 20, and 35 mg/kg), HCI (0.01N), quinacrine (10 mg/kg), nitrogen mustard (0.2 mg/kg), bleomycin (1.5 mg/kg), or NaOH (0.5%). All sclerosing agents produced a neutrophil-predominant, exudative pleural effusion within 12 h of instillation. By 48 h the pleural fluid was predominantly mononuclear. Despite the large pH range of the sclerosing agents (tetracycline, 2.0; NaOH, 13.0), the pleural fluid pH was always between 7.40 and 7.49 during the 144-h observation period. There was no difference in protein concentration, leukocyte count, or neutrophil differential with either the 3 different doses of tetracycline or the 5 other sclerosing agents. Autopsies at 30 days showed that only the 35 mg/kg dose of tetracycline produced pleural symphysis. We concluded that the common sclerosing agents produce a similar type of pleural effusion, but only tetracycline leads to pleural fibrosis; this effect appears to be dose-dependent. The pH of the sclerosing agent per se probably has little effect on the development of pleural symphysis.     

Erythromycin-induced suppression of pulmonary antibacterial defenses. A potential mechanism of superinfection in the lung

Erythromycin is a broad-spectrum antibiotic commonly used in patients with respiratory infections. Certain of these patients become colonized with new microorganisms and develop superinfections. Antibiotics have a number of effects other than simply killing or inhibiting the growth of bacteria and may have direct effects upon host cells, including phagocytes. In vitro and in vivo studies have demonstrated that erythromycin decreases polymorphonuclear leukocyte (PMN) directed migration. To test the hypothesis that erythromycin inhibits normal PMN migration into the alveoli in response to a bacterial challenge, mice were challenged by aerosol inhalation with Proteus mirabilis or Staphylococcus aureus and injected intravenously with erythromycin (50 or 100 mg/kg). Pulmonary bactericidal activity and total lavaged lung cell and differential counts were determined 4 h after bacterial challenge. In control mice, only 24 +/- 2% of the initial inoculum of P. mirabilis was viable at 4 h. At a dose of 100 mg/kg, lung defenses after erythromycin were ablated, allowing the proliferation of P. mirabilis to 113 +/- 5% of the initial inoculum. The number of PMN obtained by lavage after P. mirabilis challenge was also inhibited by erythromycin in a dose-dependent manner. In untreated animals, 5.0 +/- 0.2 x 10(6) PMN were recovered as compared with 3.1 +/- 0.4 x 10(6) and 1.1 +/- 0.3 x 10(6) with increasing doses of erythromycin. Intrapulmonary bactericidal activity against S. aureus was not impaired by erythromycin.(ABSTRACT TRUNCATED AT 250 WORDS)     

The costs of family caregiving: implications for geriatric oncology

Older adults with cancer receive considerable care from their family members. The article reviews the types of stressors family members face while caregiving, and what is known about the psychological, physical health, social, and economic costs of caregiving. The benefits experienced by caregivers, and sustained effects on families after bereavement or cancer survivorship are also reviewed. Interventions that are promising in decreasing the costs of caregiving, and implications for research and clinical practice are discussed.     

Dose-dependent effect of glucocorticosteroids on pulmonary defenses in a steroid-resistant host

An experimental model of Listeria monocytogenes pneumonia was employed in order to study the pathogenesis of lung infection with a facultative intracellular pathogen in normal and steroid-treated hosts. Guinea pigs, which resemble humans as a "steroid-resistant" species, were treated with week-long regimens of cortisone acetate or saline. Cortisone regimens were 100 mg/kg/day (low-dose) or 200 mg/kg/day (high-dose). Lungs were then infected with Listeria monocytogenes, and groups were compared for survival as well as intrapulmonary killing of Listeria. A dose-dependent defect in pulmonary resistance to Listeria was observed among the steroid-treated animals, with survivals of 67% for the low-dose group and 0% for the high-dose group. Similarly, acquired in vivo pulmonary resistance to Listeria was diminished in steroid-treated animals, as reflected by reduced intrapulmonary killing and a tendency for systemic dissemination of Listeria. Numbers of T-lymphocytes in blood (p less than 0.001) and lungs (p less than 0.001) were significantly reduced in cortisone-treated animals. In addition, alveolar macrophages obtained from high-dose-treated animals displayed a 47% reduction in listericidal activity. It is concluded that glucocorticosteroid administration causes a dose-dependent reduction in pulmonary defenses to intracellular pathogens in the steroid-resistant host, and that suppression of both acquired local immunity as well as nonimmune defense mechanisms occurs.     

Ischemic preconditioning: implications for the geriatric heart

Ischemic preconditioning is among the most consistent and powerful modes of reducing myocardial infarct size. Although several clinical studies have suggested that the human heart can be preconditioned, controversy exists in both the experimental and clinical literature as to whether the senescent heart can be preconditioned. The authors recently reported that older patients (≥60 years of age) in the Thrombolysis in Myocardial Infarction-4 study appeared to benefit from a history of angina prior to acute myocardial infarction. This observation may lead to a clinical counterpart to successful preconditioning in the older heart.     

Atrial fibrillation: management for the geriatric patient

Atrial fibrillation is one of the most common rhythm disorders encountered in the geriatric population. The diagnosis is well established, but the treatment has undergone many changes. Many long-held notions have been challenged and new treatment options, both medical and procedural, have offered new hope in the management of this disease in the elderly. This review will describe atrial fibrillation from its diagnosis to the common and more cutting-edge treatment modalities with special focus on the elderly population.     

The UKPDS: implications for the dyslipidaemic patient

The UK Prospective Diabetes Study (UKPDS) is the largest intervention trial to date of patients with type 2 diabetes, involving 5102 newly diagnosed diabetic patients. Results showed that 59% of patient deaths were from cardiovascular disease. While intensive treatment of glucose produced a significant 25% reduction in microvascular endpoints compared with diet only (p=0.0099), patients with type 2 diabetes usually have a lipid profile that is highly atherogenic. In the UKPDS, intensive treatment of hyperglycaemia and hypertension did not improve lipid levels. In patients without diabetes, lipid-lowering therapy has been shown to reduce the risk of cardiovascular events in both primary and secondary prevention trials. Currently, a number of large-scale trials of lipid-lowering therapy in patients with diabetes are ongoing. For example, the Lipids in Diabetes Study will determine whether lipid lowering with a statin or fibrate can substantially reduce cardiovascular morbidity and mortality in 5000 patients with type 2 diabetes. The Atorvastatin Study for the Prevention of coronary heart disease ENdpoints (ASPEN) is comparing double-blind treatment with atorvastatin and placebo in 2250 US diabetic patients without coronary heart disease, while a sister trial in the UK, the Collaborative AtoRvastatin Diabetes Study (CARDS), is enrolling 1820 diabetic patients. The results from these trials may provide information that which will help determine the future management of diabetic dyslipidaemia.     

The UKPDS: implications for the dyslipidaemic patient

The UK Prospective Diabetes Study (UKPDS) is the largest intervention trial to date of patients with type 2 diabetes, involving 5102 newly diagnosed diabetic patients. Results showed that 59% of patient deaths were from cardiovascular disease. While intensive treatment of glucose produced a significant 25% reduction in microvascular endpoints compared with diet only (p=0.0099), patients with type 2 diabetes usually have a lipid profile that is highly atherogenic. In the UKPDS, intensive treatment of hyperglycaemia and hypertension did not improve lipid levels. In patients without diabetes, lipid-lowering therapy has been shown to reduce the risk of cardiovascular events in both primary and secondary prevention trials. Currently, a number of large-scale trials of lipid-lowering therapy in patients with diabetes are ongoing. For example, the Lipids in Diabetes Study will determine whether lipid lowering with a statin or fibrate can substantially reduce cardiovascular morbidity and mortality in 5000 patients with type 2 diabetes. The Atorvastatin Study for the Prevention of coronary heart disease ENdpoints (ASPEN) is comparing double-blind treatment with atorvastatin and placebo in 2250 US diabetic patients without coronary heart disease, while a sister trial in the UK, the Collaborative AtoRvastatin Diabetes Study (CARDS), is enrolling 1820 diabetic patients. The results from these trials may provide information that which will help determine the future management of diabetic dyslipidaemia.     

The neurotoxicity of antibacterial agents

Commonly used antibacterial agents may be associated with various neurotoxic reactions. Central nervous system toxicities include seizure disorders, encephalopathy, bulging fontanelles, and neuropsychiatric symptoms. These abnormalities have been associated with the use of the penicillins, cephalosporins, sulfonamides, tetracyclines, chloramphenicol, colistin, aminoglycosides, metronidazole, isoniazid, rifampin, ethionamide, cycloserine, and dapsone. Cranial nerve toxicities, such as myopia, optic neuritis, deafness, vertigo, and tinnitus, have been associated with the use of erythromycin, sulfonamides, tetracyclines, chloramphenicol, colistin, aminoglycosides, vancomycin, isoniazid, and ethambutol. Peripheral nerve symptoms consisting of paresthesias, motor weakness, or sensory impairment have been associated with the use of the penicillins, sulfonamides, chloramphenicol, colistin, metronidazole, isoniazid, ethionamide, and dapsone. Neuromuscular blockade has been associated with the use of the tetracyclines, polymyxins, lincomycin, clindamycin, and aminoglycosides. Management generally consists of supportive therapy and immediate discontinuation of therapy with the offending drug.