Ofloxacin in community-acquired lower respiratory infections. A comparison with amoxicillin or erythromycin.

Ninety-one patients with community-acquired lower respiratory infections were treated orally in a comparative 10-day trial of ofloxacin versus amoxicillin or erythromycin. Approximately one-half of the patients had no major underlying disease and the other half had some form of chronic lung disease. Pneumonia was present in 31 percent of the patients and the remainder had purulent bronchitis. Bacterial pathogens were recovered from 60 percent of the patients, with Haemophilus influenzae (33 isolates) and Streptococcus pneumoniae (16 isolates) being the most common. Ofloxacin was found to be a safe, well-tolerated therapeutic agent, which was as effective clinically as amoxicillin or erythromycin and with an advantage of less frequent administration. Ofloxacin was more effective than amoxicillin (90 percent versus 75 percent; p = 0.05) in elimination of pathogenic bacteria from lower airway cultures. Caution should be exercised in the use of ofloxacin, at least in short-term treatment regimens, with anaerobic pulmonary infections; additional information is needed for S. pneumoniae given the relatively high minimal inhibitory concentrations for this species.

Asbestos exposure results in increased lung procoagulant activity in vivo and in vitro.

Enhanced fibrin deposition is a common histologic finding in fibrotic lung disorders including asbestosis and may be an important mechanism by which fibroblast proliferation is modulated. Asbestos-induced activation of lung interstitial cells may result in enhanced expression of procoagulant activity which contributes to the inflammatory response resulting in subsequent fibrin deposition. The current study examines procoagulant activity in bronchoalveolar lavage fluid from patients with clinically diagnosed asbestosis, patients with asbestos exposure without asbestosis, and normal, control subjects. Results indicated that asbestos exposure resulted in increased lung procoagulant expression in vivo, and furthermore, suggested that both endothelial cells and alveolar macrophages represented lung parenchymal cells which may contribute to this activity. This imbalance in coagulation homeostasis may be important in the regulation of fibrotic responses observed in asbestosis.

Reduced diffusing capacity as an isolated finding in asbestos- and silica-exposed workers.

From a cohort of 286 patients referred to an Occupational Medicine Clinic because of exposure to asbestos and/or silica, we identified 53 patients with a reduced diffusing capacity (Dco) (less than 75 percent predicted) as their only abnormality. Specifically, their clinical evaluation, chest roentgenograms, and remaining pulmonary function test results were all normal. These patients were divided into non-smokers (n = 13) and smokers (n = 40). The significance of the isolated reduction in diffusing capacity in these patients (n = 53) was explored with graded exercise testing (n = 19) and bronchoalveolar lavage (BAL) (n = 50). The results obtained from the patients with reduced diffusion were compared with those obtained from comparable smoking (n = 35) and nonsmoking patients (n = 37) in the original cohort who had normal chest roentgenograms and normal results of pulmonary function studies, including normal Dco values (greater than or equal to 75 percent of predicted value). Patients with low diffusion demonstrated a tendency for elevated alveolar to arterial O2 differences both at rest and during exercise, and a significant reduction in exercise capacity (VO2 max) was observed in the smoking patients with reduced diffusion when compared with their smoking counterparts with normal diffusion. All other exercise testing indexes were normal in the study groups and there was no correlation between the percent predicted Dco value and any of the exercise variables. In contrast, BAL revealed significant differences between patient groups. Both the smoking and nonsmoking patient groups with low Dco values had greater numbers of total BAL cells, alveolar macrophages, neutrophils, lymphocytes, and eosinophils in their BAL fluid than did their comparable controls with normal diffusion values. These differences were statistically significant (p less than .05) for total BAL cells and total macrophages in the nonsmoking patients and for total BAL cells, total macrophages, and total lymphocytes in the smoking patients expressed as either the total cell number per BAL or total cells per milliliter of BAL. In contrast to the observed exercise testing results, there was significant and inverse correlation between Dco values and each BAL cell type for all four groups combined as well as nonsmokers alone. The Dco values from smokers were significantly and inversely correlated with total BAL cells and total macrophages. These results suggest that the finding of a reduced Dco may be related to an active inflammatory process in the lung caused by occupational dust exposure.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of isoniazid-resistant tuberculosis in southeastern Texas.

BACKGROUND: Isoniazid-resistant tuberculosis (INHr-TB) can be treated successfully with several treatment regimens. However, the optimal regimen and duration are unclear. STUDY OBJECTIVE: To analyze the efficacy of treatment regimens used for INHr-TB in the southeastern Texas region. DESIGN: Retrospective cohort study. SETTING: Health-care facilities reporting tuberculosis (TB) patients in the Houston and Tyler areas. SUBJECTS: All patients reported to have INHr-TB from 1991 to 1998. Exclusion criteria included poor compliance, additional first-line drug-resistance (except aminoglycosides), and death before completion of 1 month of treatment. MEASUREMENTS AND RESULTS: Main treatment outcomes were treatment failure, relapse, and TB-related death. Fifty-three of 83 patients were included in the study; aminoglycoside resistance coexisted in 37.5% of isolates. Seven types of treatment regimens were identified. Eighteen patients (34%) received rifampin, pyrazinamide, and ethambutol thrice weekly for 9 months. Four patients (7.5%) had a total effective treatment duration of < 9 months. Thirty patients (56.6%) and 16 patients (30.2%) received thrice-daily and daily treatment regimens, respectively. Forty-nine patients achieved sputum conversion. Treatment failure and death occurred in one patient (1.9%). Three patients (5.7%) experienced relapses. There was a significant difference in total effective treatment time between patients with and without relapses (8.3 +/- 1.1 months vs 11.1 +/- 2.1 months; p < 0.02). Twice-weekly treatment regimens were associated with relapse (p = 0.05). CONCLUSIONS: Several treatment regimens were prescribed for INHr-TB in southeastern Texas. INHr-TB treatment durations were > 7 months, and treatment regimen efficacy was adequate. Twice-weekly treatment was associated with relapse, whereas thrice-weekly and daily treatments performed similarly. A prospective study with different treatment durations is needed to determine the optimal treatment regimen for patients with INHr-TB.

Hyperoxic exposure in humans. Effects of 50 percent oxygen on alveolar macrophage leukotriene B4 synthesis.

The pathogenesis of oxygen toxicity remains unknown but may involve leukocyte mediated injury. The effects of hyperoxia on several lower respiratory tract parameters were examined in bronchoalveolar lavage fluid of normal nonsmoking subjects who inhaled a fractional inspired oxygen concentration of 50 percent (mean exposure: 44 h). Evidence that 50 percent O2 produced oxidative stress in the lung included recovery of fluorescent products of lipid peroxidation and partial oxidation of alpha 1-antitrypsin in BAL fluid obtained after O2 exposure. To examine whether alveolar macrophage-derived leukotriene B4 may be generated in response to 50 percent O2, AM were isolated from O2-exposed subjects and compared with AM recovered from subjects breathing room air. Leukotriene B4 levels were elevated in supernatants from both unstimulated and arachidonic acid-stimulated AM obtained from hyperoxia-exposed subjects. In hyperoxia-exposed individuals, LTB4 levels were also elevated in extracted BAL fluid. The percentage of BAL neutrophils was also significantly increased after O2 exposure (2.8 +/- 0.6 vs 1.2 +/- 0.4 percent, p = 0.05). We conclude that an FIO2 of 50 percent inhaled for 44 h is associated with enhanced oxidative stress, stimulation of AM to release LTB4, and a small but significantly increased percentage of neutrophils recovered in BAL fluid.

Differential effects of salmeterol on lung endothelial and epithelial leakage in sheep.

Salmeterol has been shown to prevent the influx of proteins into the air spaces of lungs of guinea pigs given intravenous histamine. To determine whether the salmeterol acts to stabilize the epithelial or endothelial barrier, we ventilated anesthetized sheep with aerosolized salmeterol before infusing histamine intravenously at a rate of 4 micrograms.kg-1.min-1 for 3 h. Changes in endothelial permeability were assessed by measuring the flow of lymph and proteins from the lungs. The influx of proteins into the air spaces was detected by performing single-cycle lavages to measure the concentration of circulating 125I-albumin in the epithelial lining fluid. Intravenous histamine increased the lymph flow to 13.2 +/- 6.8 ml/h compared with the control value of 5.6 +/- 2.8 ml/h (P < 0.05). Histamine also increased the concentration of 125I-albumin in the epithelial lining fluid from 1.8 +/- 0.9 to 8.5 +/- 2.5% of the plasma concentration (P < 0.01) and the postmortem lung water volume from 3.5 +/- 0.5 to 5.0 +/- 0.8 mg/g dry lung wt (P < 0.05). Pretreatment with 2.5 mg of aerosolized salmeterol prevented the influx of proteins into the air spaces and the increase in the postmortem lung water volume but it also increased the lung lymph flow even further to 20.0 +/- 5.6 ml/h (P < 0.05), increased the lymph-to-plasma protein ratio from 0.77 to 0.91, and tripled the increase in alveolar-arterial oxygen gradient caused by histamine alone. Pretreatment with 2.5 mg of intravenous salmeterol had essentially the same effect as salmeterol administered by aerosol. We conclude that salmeterol decreases lung epithelial permeability but increases lung endothelial permeability due to intravenous histamine in sheep.

Mycobacteria as pathogens of respiratory infection.

As the result of a formidable effort, the recent TB epidemic in the United States has abated; however, major questions remain as the risk of TB diminishes. Will we maintain an adequate public health effort not only to prevent another resurgence of TB but also to renew our pursuit of TB elimination? Do we have the will to extend the fight against TB worldwide as the TB threat in the United States declines? What is the best way to incorporate new diagnostic technology into routine practice? What are the best strategies for preventing and treating TB in AIDS patients? From the standpoint of NTM lung diseases, the major challenges are to educate clinicians about the variety and clinical presentation of NTM lung pathogens in order to recognize NTM lung disease as early as possible and to maximize treatment options. Hopefully, we can also improve upon the recent unprecedented progress in treatment regimens for NTM diseases of all types.

Pneumonia in chronic obstructive lung disease.

Despite the apparent common occurrence of pneumonia in patients with chronic obstructive pulmonary disease (COPD), there are little firm data on incidence, etiology, diagnostic procedures, and therapy in these patients. It appears that traditional respiratory pathogens such as the pneumococcus are declining in importance while "new" pathogens such as Pseudomonas sp., Moraxella catarrhalis, and Legionella sp. are becoming more important. The diagnosis of a specific etiologic agent is difficult in COPD and can be aided by obtaining specimens bronchoscopically. Directed therapy is optimal; however, empiric therapy is frequently unavoidable.

Drug intolerance to high-dose clarithromycin among elderly patients.

We treated 13 elderly patients with chronic mycobacterial lung disease with clarithromycin using 1000 mg b.i.d. as monotherapy. Patients had a mean age of 70 years, and 12 of 13 had creatinine clearances of 31-71 ml/min. Adverse events were seen in 100% of patients, with the most common being bitter taste (92%), nausea (92%), vomiting (54%) and central nervous system symptoms (54%). Elevated liver enzymes developed in five (38%) of 13 patients at weeks 1-6 of therapy. Mean serum levels of clarithromycin plus its 14-OH metabolite were 12.9 +/- 3.6 micrograms/ml (SD). There were 11 patients (85%) who discontinued the high dose within 3 months because of side effects. Serum drug levels of clarithromycin plus its 14-OH metabolite consistently exceeded 12 micrograms/ml in six of six patients who discontinued drug (10 of 10 values) compared with neither of two patients who tolerated the high dose (0 of 6 values). A dose reduction to 500 mg b.i.d. was well tolerated (nine of 10 patients). Future trials with clarithromycin in this population should use lower doses with attention to body mass and renal function to minimize side effects.

Risk-benefit assessment of therapies for Mycobacterium avium complex infections.

Mycobacterium avium complex (MAC) is an important pathogen that can cause chronic lung disease in immunocompetent patients and disseminated disease in patients with the acquired immunodeficiency syndrome (AIDS). Treatment of MAC with antituberculosis drugs was unsatisfactory, but the introduction of the newer macrolides, clarithromycin and azithromycin, and of rifabutin has greatly improved the outcome of treatment regimens for MAC. However, these agents are also associated with many new treatment-related adverse effects and potential drug-drug interactions. Rifamycins [rifampicin (rifampin) more than rifabutin] induce cytochrome P450 enzymes and accelerate the metabolism of clarithromycin and HIV protease inhibitors. Conversely, clarithromycin inhibits these enzymes, resulting in increased rifabutin toxicity. The net results are treatment regimens that may be extremely difficult to tolerate, especially for elderly or debilitated patients. Clarithromycin and azithromycin must be administered in combination with other agents such as ethambutol to prevent the emergence of macrolide resistance. Unfortunately, not all patients respond to the combination of a macrolide, rifabutin and ethambutol, and many have significant adverse effects (mostly gastrointestinal) with this regimen. For some patients the treatment is worse than the disease. The same 3-drug regimen is also effective therapy for disseminated MAC in AIDS patients, in whom the additional problem of a rifamycin/protease inhibitor interaction may be present. Fortunately, as opposed to pulmonary MAC disease in immunocompetent patients, disseminated MAC disease is a diminishing problem because of effective prophylactic regimens for MAC and improved antiretroviral therapy for HIV. Significant progress has been made in the treatment of MAC disease with the introduction of the newer macrolides. It is to be hoped that even better drugs that are more active against MAC and are associated with less toxicity and drug-drug interactions will be introduced in the future.

Results of operation in Mycobacterium avium-intracellulare lung disease.

BACKGROUND: Although operation remains part of the management of Mycobacterium avium-intracellulare lung disease, few series have assessed operation in the era of better therapeutic drugs (especially clarithromycin). METHODS: From January 1, 1989, through June 30, 1997, 28 patients with M avirum-intracellulare lung disease underwent pulmonary resection. All were receiving multidrug therapy (17 of 28 were receiving clarithromycin) before and after operation. Eight patients underwent pneumonectomy (6 right, 2 left); 20 patients underwent partial resections including 18 with upper lobe lobectomies (14 right, 4 left). The most common indications for operation were medical treatment failure (15) and as part of initial therapy (9). RESULTS: Mean postoperative follow-up was 39 months. Complications occurred in 9 of 28 patients (32%), and included persistent air leak requiring surgical correction (5), early postoperative death (2), and late bronchopleural fistulae (1 patient). Twenty-three of 26 patients were known to be acid fast bacilli culture negative within 1 month of operation. Only 1 of 26 patients who survived 2 years is known to have had a relapse. CONCLUSIONS: Operation continues to play an important role in treatment of M avium-intracellulare lung disease. More than 90% of patients become culture negative and remain so when they continue to receive drugs. Although morbidity is relatively high, it is manageable and the 12-month mortality in the current series was low (7%).

Growth factors for human pleural mesothelial cells in soluble products from formed clots.

Fibrin deposition within the pleural space may influence repair following pleural injury. Although the mesothelial surface can organize fibrin, the contribution of pleural mesothelial cells to pleural repair is unknown. During coagulation thrombin cleaves Fibrinopeptide A (FPA, A alpha 1-16) and fibrinopeptide B (FPB) from the A alpha and B beta chains of fibrinogen to generate fibrin monomer. Since these peptides are mitogenic for human fibroblasts, we considered that they might stimulate replication of human pleural mesothelial cells (HPMC). Application of fluid expressed from fibrin clots significantly increased cell number and stimulated uptake of 3H-thymidine by HPMC compared with untreated cells. The mitogenic response of subconfluent HPMC to dilutions of clot fluid (30-150 micrograms/ml protein) was comparable to that of 0.1 nM TGF-beta. Fibrinopeptide A (7.5-30 microM) stimulated 3H-thymidine uptake in HPMC, but FPB had only a slight effect at 30 microM. Antibody to FPA antibody significantly attenuated the mitogenic effect of clot fluid, indicating that a major component is FPA. Our study suggests that fibrinopeptides released during fibrin formation in vivo may stimulate local mesothelial regeneration following pleural injury.

Respiratory effects of outdoor air pollution.

Outdoor air pollution adversely affects human health and the quality of the environment. However, epidemiologic studies of these effects are difficult to control because of confounding variables such as age and cigarette smoking and the difficulty in estimating doses of pollutants. Drs Griffith and Levin discuss the relationship between major types of pollutants and increased morbidity and mortality from respiratory disease.

Chronic bronchitis. Key points in evaluation.

Thorough history taking is essential in evaluation of chronic bronchitis. Patients often reveal key symptoms that help define the disorder and provide information about contributing factors, such as cigarette smoking, that can be eliminated. Useful baseline data can be collected through pulmonary function studies, electrocardiogram, chest radiographs, complete blood cell count, and measurement of electrolyte levels.

Chronic bronchitis. Choosing the optimal treatment.

Among the various therapies for chronic bronchitis none is more important, both for relieving symptoms and for preserving pulmonary function, than cessation of cigarette smoking. Unfortunately, even when patients are motivated and programs are aggressive, results are unspectacular. Chronic bronchitis often responds favorably to bronchodilating agents. For initial therapy, ipratropium bromide (Atrovent) is the agent of choice because of its efficacy and safety. The role of antiinflammatory drugs is not yet clear, although inhaled steroids are beneficial in some patients. Most patients improve with smoking cessation and/or judicious pharmacologic intervention.

A tuberculosis hotline in Tyler: a Texas resource for primary health care providers for the control of infectious diseases.

The Center for Pulmonary and Infectious Disease Control (CPIDC), located on the campus of The University of Texas Health Center in Tyler, manages a toll-free infectious disease consultation hotline advertised to public and private physicians and to health care agencies throughout the state. From January 1994 through December 1996, as part of a statewide initiative to curb an unprecedented increase in the incidence of tuberculosis observed since 1985, a concentrated effort was made to solicit health care providers for consultation requests that involved the diagnosis and management of tuberculosis, in particular, drug-resistant varieties. During that period, 3447 calls were made to the CPIDC by 1682 physicians and nurses. While most of the calls originated from 4 major urban areas plus health care facilities along the border, calls were received from more than half of all the counties in Texas. The value of providing an infectious disease consultation service, readily available, without charge, to all members of the health care community is discussed.