The effect of azithromycin and clarithromycin on ex vivo interleukin-8 (IL-8) release from whole blood and IL-8 production by human alveolar macrophages.

We investigated the effects of azithromycin and clarithromycin, two antibiotics that possess a broad spectrum of antimicrobial activity (including antimycobacterial activity), on interleukin-8 (IL-8) release from human whole blood leucocytes and lung macrophages. Ex vivo stimulation of leukocytes with either of the antibiotics (0.04-40 mg/L) significantly increased IL-8 secretion. Incubation of alveolar macrophages with different concentrations of azithromycin or clarithromycin modified IL-8 production: it increased at a drug concentration of 4 mg/L and decreased at concentration of 400 mg/L. Our findings suggest that azithromycin and clarithromycin may alter IL-8 production, thus enhancing the clinical effectiveness of these antibiotics.

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.

Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease.

Ninety-two patients were assessable in 3 consecutive, open, noncomparative, prospective, controlled, single-center trials of the use of multidrug regimens that contain azithromycin for treating pulmonary Mycobacterium avium complex (MAC) disease. Azithromycin was provided at a dose of 300-600 mg per day with oral companion drugs administered daily (regimen A, 29 patients); 600 mg 3 times weekly (t.i.w.), with oral companion drugs administered daily (regimen B, 20 patients); and 600 mg (t.i.w.), with oral companion drugs administered t.i.w. (regimen C, 43 patients). All regimens included rifabutin (or rifampin) and ethambutol as companion drugs as well as initial streptomycin. Treatment success was defined as 12 months of negative cultures while on therapy. Treatment failure was defined as sputum culture positivity after at least 6 months of therapy. Of the patients in each regimen who reached study end points, 17 of 29 (59%) were in regimen A, 11 of 20 (55%) were in regimen B, and 28 of 43 (65%) were in regimen C met the treatment success criterion. There were no statistically significant differences in outcome between the 3 regimens. These studies demonstrate the effectiveness of daily and t.i.w. regimens containing azithromycin for treatment of MAC lung disease.

T cells enhance production of IL-18 by monocytes in response to an intracellular pathogen.

We studied the effect of T cells on IL-18 production by human monocytes in response to Mycobacterium tuberculosis. Addition of activated T cells markedly enhanced IL-18 production by monocytes exposed to M. tuberculosis. This effect was mediated by a soluble factor and did not require cell-to-cell contact. The effect of activated T cells was mimicked by recombinant IFN-gamma and was abrogated by neutralizing Abs to IFN-gamma. IFN-gamma also enhanced the capacity of alveolar macrophages to produce IL-18 in response to M. tuberculosis, suggesting that this mechanism also operates in the lung during mycobacterial infection. IFN-gamma increased IL-18 production by increasing cleavage of pro-IL-18 to mature IL-18, as it enhanced caspase-1 activity but did not increase IL-18 mRNA expression. These findings suggest that activated T cells can contribute to the initial immune response by augmenting IL-18 production by monocytes in response to an intracellular pathogen.

Cytokine profiles in immunocompetent persons infected with Mycobacterium avium complex.

To evaluate the immunologic factors that contribute to protection against Mycobacterium avium complex (MAC), cytokine production by peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus-negative persons with pulmonary MAC (MAC patients) and healthy control subjects with a delayed hypersensitivity skin test response to M. avium sensitin (MAS-positive control subjects) was measured. In MAC patients, mycobacterium-stimulated PBMC produced higher concentrations of interleukin (IL)-10 but lower concentrations of interferon (IFN)-gamma, IL-12, and tumor necrosis factor (TNF)-alpha, compared with PBMC from MAS-positive control subjects. Immunolabeling for intracellular IL-10 revealed that this cytokine was produced by both monocytes and T cells. Alveolar macrophages produced TNF-alpha and IL-10 in response to MAC, which suggests that these cytokines are produced in the lungs of patients with pulmonary disease caused by this pathogen. Our findings suggest that IFN-gamma, TNF-alpha, and IL-12 contribute to protection against MAC, whereas IL-10 is immunosuppressive.

Modulation by pentobarbital of neutrophil responses to inhaled E. coli endotoxin in sheep: role of lung epithelium.

Neutrophils (PMNs) are implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). The role of the epithelium in the modulation of PMN migration within the lungs was examined. Epithelial integrity and PMN concentrations in the lung air spaces and lymph were measured in sheep anaesthetized with either halothane (1-2.5%) or intravenous pentobarbital (12+/-4 mg x kg(-1) x h(-1)). Ventilation with an aerosol containing 25 mg Escherichia Coli endotoxin (lipopolysaccharide; LPS) effected neutrophil recruitment to the air spaces. Lymphatic clearance of aerosolized 99mTc-DTPA provided an index of epithelial integrity. Three hours after the deposition of LPS, the lung lining fluid of sheep anaesthetized with halothane (n=7) had 4.9+/-3.2x10(6) PMN.mL(-1), but the lung lymph had almost no PMNs (3+/-8%). Sheep anaesthetized with pentobarbital (n=6) had fewer PMNs in the air spaces (2.4+/-1.2X10(6) mL(-1)) and more PMNs in the lung lymph (30+/-20%). Control sheep (n=5) that received no LPS had almost no PMNs in the airspaces or lung lymph, regardless of the anaesthesia. Three additional sheep that remained awake after receiving LPS also had no PMNs in the lung lymph. The PMN fraction in the lung lymph correlated well with the extra-alveolar epithelial permeability measured by lymphatic clearance of aerosolized diethylenetriamine penta-acetic acid (r=0.81, p<0.001). Aerosolized lipopolysaccharide recruits neutrophils into the lungs of sheep, but they appear to remain in the airspaces unless extra-alveolar permeability is increased by agents such as pentobarbital.

Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex.

We initiated a prospective noncomparative trial of treatment for lung disease due to Mycobacterium avium complex (MAC) in human immunodeficiency virus-negative patients, with a regimen of clarithromycin (1000 mg), rifabutin (300-600 mg), and ethambutol (25 mg/kg) administered 3 times per week. Fifty-nine patients were enrolled. Twelve (20%) were lost to follow-up, and 6 (10%) developed clarithromycin intolerance. The remaining 41 patients (69%) completed the initial 6 months of therapy. The sputum of 32 of these patients (78%) converted to negative. When results were compared with the sputum response rates at 6 months in previous studies with a regimen including daily clarithromycin and regimens including intermittent (3 times per week) azithromycin with the same companion drugs, no differences in treatment responses were evident. Adverse reactions related to rifabutin were a major problem, and for 24 (41%) of 59 patients the dosage was decreased or the drug was withdrawn. Intermittent (3 times per week) administration of clarithromycin appears to be as effective as daily administration in effecting sputum conversion in pulmonary MAC disease.

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.

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.

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.

Polyclonal Mycobacterium avium complex infections in patients with nodular bronchiectasis.

Mycobacterium avium complex (MAC) isolates among patients with chronic lung disease were studied for their heterogeneity using genetic identification methods, pulsed field gel electrophoresis (PFGE) and seroagglutination. A mean of 7.3 cultures per patient were collected from 17 patients with nodular bronchiectasis who were elderly (mean age 66 yr), predominantly female (76%), had smoked a mean of only 5 pack-years, and had multifocal bronchiectasis. A mean of 7.7 cultures per patient were collected from nine patients with upper lobe cavitary disease who were younger (mean age 52 yr), predominantly male (78%), and heavy smokers (mean 56 pack-yr). A mean of 2.9 PFGE types (genotypes) per patient (range, 1 to 9) were identified in the nodular bronchiectasis group, with 15 of 17 patients (88%) having two or more genotypes and 9 of 17 (53%) having three or more genotypes. In contrast a mean of 1.2 genotypes were identified in the patients with cavitary disease, with only 1 of 9 (11%) having two or more genotypes. Mycobacterium intracellulare was the most frequently recovered genotype in both groups and most isolates were rough or nontypable by seroagglutination. Some genotypes from the same patient considered different by current PFGE criteria had the same serotype and shared 11 to 20 common PFGE bands, suggesting they were related. These data demonstrate that patients with nodular bronchiectasis have multiple and/or repeated infections due to MAC whereas patients with upper lobe cavitary disease are usually infected with only a single strain.

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%).

Initial (6-month) results of three-times-weekly azithromycin in treatment regimens for Mycobacterium avium complex lung disease in human immunodeficiency virus-negative patients.

Two consecutive, open, prospective trials of intermittent azithromycin (600 mg), usually given Monday, Wednesday, and Friday (TIW) for Mycobacterium avium complex (MAC) lung disease were initiated in human immunodeficiency virus-negative patients. Regimen A consisted of TIW azithromycin and daily ethambutol (15 mg/kg/day), daily rifabutin (300 mg/day), and initial twice weekly (BIW) streptomycin. Regimen B consisted of TIW azithromycin, TIW ethambutol (25 mg/kg/dose), TIW rifabutin (600 mg/dose), and initial BIW streptomycin. Of 19 patients enrolled in regimen A who completed at least 6 months of therapy, 14 (74%) had sputum samples become culture-negative. Of 39 patients enrolled in regimen B who completed at least 6 months of therapy, 24 (62%) had sputum conversion. These sputum conversion rates are comparable to previous rates at 6 months in patients receiving daily clarithromycin- or azithromycin-containing regimens. No resistance to azithromycin emerged with either regimen. This is the first study to demonstrate the efficacy of intermittent administration of medication for MAC lung disease.

Sensitivity of fluorochrome microscopy for detection of Mycobacterium tuberculosis versus nontuberculous mycobacteria.

The results for 6,532 consecutive mycobacterial respiratory specimens collected from 1,040 patients from 1993 to 1995 in a Texas hospital were studied to determine the sensitivity of fluorescence microscopy for detection of Mycobacterium tuberculosis and nontuberculous mycobacteria (NTM). Smears were positive for acid-fast bacilli (AFB) in 63% (677 of 1,082) of specimens growing M. tuberculosis and 56% (638 of 1,148) of specimens growing the four most common species of NTM. Smear positivity by species was 58% (446 of 776) for M. avium complex, 51% (154 of 300) for rapidly growing mycobacteria (98% were M. abscessus), 78% (29 of 37) for M. kansasii, and 26% (9 of 35) for M. gordonae. Definite or probable disease by clinical criteria was present in 79% of patients with M. avium complex, 93% of patients with rapidly growing mycobacteria, 100% of patients with M. kansasii, and 0% of patients with M. gordonae. Patients with M. avium complex had a low incidence of AIDS (7%), and approximately 50% of non-AIDS patients had upper-lobe cavitary disease and 50% had nodular bronchiectasis. Only 23 of 6,532 (0.35%) of AFB smears were positive with a negative culture excluding patients on therapy for established mycobacterial disease. These studies suggest that NTM are as likely as M. tuberculosis to be detected by fluorescent microscopy in specimens from patients from areas endemic for NTM lung disease and at low risk for AIDS.

Clearance of proteins from the air spaces following cardiogenic edema in sheep.

Studies on the clearance of instilled fluid and protein into the lungs of sheep show that fluid initially clears rapidly from the lungs resulting in an increase in an increase in air space protein concentrations. This is followed by a slower monoexponential clearance of proteins during the next few days. To determine whether the clearance of edema fluid follows the same time course as instilled fluid, alveolar edema was induced in 11 sheep by inflating a balloon in the left atrium for 2 h to increase left atrial pressure 35-40 cm H2O. Protein concentrations in the epithelial lining fluid (ELF) were monitored by performing single-cycle lavages immediately after deflation of the left atrial balloon, and again 3, 21, 48, and 96 h later. During the first 3 h of recovery, 44% of the fluid cleared and ELF protein concentrations rose from 7 +/- 2 to 19 +/- 6 mg/mL in the 7 sheep that recovered well. The ELF protein concentration in these sheep remained elevated for 48 h and then cleared at rates similar to that seen following instillation of proteins. We conclude that insights about mechanisms of clearance of edema fluid obtained from studies of clearance of instilled fluid are valid in cardiogenic edema, but the time course of the clearance differs between the two models.