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PubMed1997

Altered IL-1 expression and compartmentalization in monocytes from patients with AIDS stimulated with Mycobacterium avium complex.

The pathophysiologic basis for the exuberant intracellular growth of Mycobacterium avium complex (MAC) in AIDS patients is unclear but may relate to altered expression of modulatory cytokines. Interleukin (IL)-1, IL-6, and TNF-alpha expression by monocytes from AIDS patients and healthy subjects (HS) stimulated with isogeneic MAC strains (SmT, smooth-transparent, virulent; SmD, smooth-domed, avirulent) was examined. Spontaneous cytokine production was not observed in patients with AIDS. MAC strains induced less IL-1 alpha and IL-1 beta release in AIDS patients than HS (P < 0.05). The ratio of cell-associated to supernatant IL-1 alpha also was increased in AIDS patients (P = 0.03). IL-1 beta mRNA expression paralleled protein release in either group of subjects. In both HS and AIDS patients, stimulation with SmD induced more IL-1 and TNF-alpha release by monocytes compared to SmT. In AIDS patients, SmD also induced greater IL-6 release than SmT (P < 0.01). Alterations in monocyte expression and compartmentalization of the regulatory cytokines IL-1 and IL-6 may enhance bacterial replication and contribute to the pathogenesis of MAC infection in AIDS.

AIDS-Related Opportunistic Infections↗

PubMed1997

Electron microscopic analysis of Mycobacterium avium complex isolates exposed to ciprofloxacin, rifabutin, ethambutol and clarithromycin.

SETTING: Mycobacterium avium complex (MAC) isolates grown in the presence of clarithromycin, ciprofloxacin, ethambutol or rifabutin were examined by electron microscopy for drug-induced ultrastructural changes. OBJECTIVE: To further the understanding of the activity of clarithromycin, ciprofloxacin, ethambutol and rifabutin against MAC. DESIGN: Four MAC isolates, 1 control and 3 patient, were cultured for 24 or 72 hours in liquid medium containing one of two concentrations of an antimicrobial agent prior to examination by electron microscopy. RESULTS: One or more of the following ultrastructural changes was observed after exposure to the antimicrobial agent: disorganized nucleoid and cytoplasm, condensation of nucleoid, vacuolization, enlargement of the periplasmic space with or without vesicles, intracytoplasmic lipid-like inclusions, and cell lysis. Changes were seen after as little as 24 hours of exposure to the antimicrobial agent and were more evident with the higher of the two concentrations of the drug. Changes were present regardless of the minimum inhibitory concentration (MIC) of the antimicrobial agent against the isolates tested, but were more pronounced if the MIC was less than the concentration of drug tested. CONCLUSION: Consistent ultrastructural changes were observed following exposure to a given antimicrobial agent. No drug-specific changes were identified.

Antitubercular Agents↗

PubMed2000

Familial pulmonary Mycobacterium avium complex disease.

We report two Japanese families affected by pulmonary Mycobacterium avium complex (MAC) disease, involving an older brother and younger sister in one family and two brothers in the second family. We investigated whether defects in the natural resistance-associated macrophage protein gene (NRAMP1) underlay susceptibility to MAC in these cases. All of the patients had computed tomographic findings of peripheral nodules and bronchiectasis. Pulse-field gel electrophoresis patterns of mycobacterial genomic DNA restriction fragments revealed that none of the MAC strains isolated from the patients was epidemiologically related to any of the others. Direct sequencing of the complementary DNA of the patients' NRAMP1 revealed a nonconservative missense mutation at codon 419 in one patient, which was heterozygous and was not seen in his affected sibling. No variations similar to those found in mice that show susceptibility to MAC were found. The results suggest an underlying genetic defect in host defense rather than exposure to an unusually virulent strain of MAC as the pathogenetic factor in MAC disease; however, alterations in the coding region of NRAMP1 do not appear to explain the susceptibility to MAC.

Adult↗

PubMed1994

Rifabutin and sparfloxacin but not azithromycin inhibit binding of Mycobacterium avium complex to HT-29 intestinal mucosal cells.

Organisms of the Mycobacterium avium complex (MAC) cause disseminated disease in patients with AIDS, and evidence points to the gastrointestinal tract as the major route of infection. Since MAC can bind to and invade intestinal mucosal cells, we examined whether subinhibitory concentrations of antibiotics which have anti-MAC activity in vitro affect the interaction between MAC and HT-29 intestinal mucosal cells. MAC isolates were exposed to subinhibitory concentrations of rifabutin (MIC, 2.6 micrograms/ml), sparfloxacin (MIC, 8.4 micrograms/ml), or azithromycin (MIC, 32 micrograms/ml) for 30 to 120 min, washed, and incubated with HT-29 cell monolayers for 2 h at 4 degrees C. HT-29 cell monolayers were then washed to remove unbound bacteria and were subsequently lysed. The number of MAC isolates that bound to the HT-29 cells was determined by plating the cell lysate onto 7H10 agar. Preincubation of the MAC isolates with rifabutin at concentrations of 1 and 2 micrograms/ml reduced MAC binding to HT-29 cells by 80 to 90%, while MAC exposed to sparfloxacin at 1 and 7 micrograms/ml inhibited binding by 77 to 93%. Azithromycin at concentrations of 2, 10, and 30 micrograms/ml had no effect on MAC binding to HT-29 cells. Inhibition of MAC binding to the gastrointestinal mucosa may be one underlying mechanism for the prophylactic effects of rifabutin and quinolones.

Anti-Infective Agents↗

PubMed1998

Evaluation of in vivo therapeutic efficacy of a new benzoxazinorifamycin, KRM-1648, in SCID mouse model for disseminated Mycobacterium avium complex infection.

In this study, profiles of infection due to Mycobacterium avium complex (MAC) in CB-17 SCID mice deficient in T and B cell functions were examined, when mice were given or not given a new benzoxazinorifamycin, KRM-1648 (KRM), during the course of infection. When mice were infected intravenously with MAC, the bacterial loads in their visceral organs were larger than those of their co-isogenic CB-17 counterparts. The incidence and the degree of gross lung lesions were less in SCID mice compared to CB-17 mice. Athymic BALB/c nude mice showed similar profiles of the infection. Beige mice showed more severe gross lesions and larger bacterial loads in the lungs than did SCID and athymic BALB/c nude mice. When MAC was infected subcutaneously into the hind footpads of mice, disseminated growth of organisms in the footpads, blood, and visceral organs was seen in SCID mice, but not in CB-17 or BALB/c mice. KRM exhibited the same level of therapeutic effect on SCID mice infected with MAC via the intravenous route in terms of inhibiting bacterial growth in the lungs and kidneys, as in cases of CB-17 and BALB/c mice with normal T-cell functions. In beige mice, the degree of growth inhibition of MAC due to KRM treatment was significantly greater than that achieved in SCID mice.

Animals↗

PubMed1991

Current and investigational therapies for AIDS-associated Mycobacterium avium complex disease.

The epidemiology, pathogenesis, clinical manifestations, and treatment of Mycobacterium avium complex (MAC) infection are reviewed. MAC infection is one of the most common infections in AIDS patients. Its pathogenesis is poorly understood, but it is believed to develop by gastrointestinal colonization followed by systemic invasion. The relatively poor response to treatment may be partly accounted for by the tremendous mycobacterial load present by the time patients develop systemic symptoms. Clinically, MAC infection is difficult to differentiate from the signs and symptoms of AIDS or from other opportunistic infections. Signs and symptoms include fever, malaise, anorexia, night sweats, and weight loss; diarrhea and abdominal pain may also be present. There is no established therapy for MAC infection, although combinations of three to five antimicrobial agents are typically used. There has been consistently poor correlation between in vitro results and in vivo outcomes in the treatment of MAC infection. Currently, the role of treatment is mainly to suppress the progression of infection and to relieve symptoms. Recent in vitro studies and animal studies have revealed possible alternative agents and combinations of agents (e.g., macrolide antibiotics, quinolones, amikacin, cytokines) that may influence therapy of MAC infection. No known therapy for MAC has been shown to prolong survival in AIDS patients, possibly because of the high organism load that exists once patients become symptomatic. Research is needed to find improved methods for earlier detection of MAC infection, determine optimal dosage regimens of current antimycobacterial agents, develop better antimycobacterial drug-delivery systems (e.g., liposomes), and discover new antimicrobials with better activity against MAC and methods of immune modulation that will overcome immune system defects.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Clinical analysis of pulmonary Mycobacterium avium complex disease in association with corticosteroid treatment.

We studied the clinical characteristics of nine patients with pulmonary Mycobacterium avium complex disease occurring in association with corticosteroid drugs collected from our associated hospitals during the past 6 years. The average age of the nine patients was 62.2 years and the male/female ratio was 3 : 6. Regarding underlying disease, respiratory diseases existed in four of the patients and nonrespiratory diseases in the other five patients. The duration of corticosteroid treatment ranged from 5 months to 5 years, and the total dose of corticosteroid drugs ranged from 1.78 to 43.20 g. Pulmonary Mycobacterium avium complex disease was detected by clinical symptoms during corticosteroid treatment in six patients, and purified protein derivative was positive in three of eight patients tested. Radiological findings showed an infiltration shadow without cavity and bronchiectasis in the lower lung field. Microbiological examination was smear-positive in three patients, and the isolated mycobacterium was Mycobacterium intracellulare in five patients and Mycobacterium avium in four. Tolerance was shown to all antituberculous drugs, except for clarithromycin, in all patients. Although treatment including clarithromycin was performed for seven patients, the sputum conversion rate was 33% and an improved clinical effect was noted in only one patient. No change occurred in four and worsening occurred in four. Attention should be paid to the clinical symptoms and radiological findings of patients who have received corticosteroid drugs over a long period of time, because pulmonary Mycobacterium avium complex is characterized by atypical radiographic findings with no relationship to the total dose or duration of the administered corticosteroid drugs.

Adrenal Cortex Hormones↗

PubMed2000

Interaction of Mycobacterium avium complex with human respiratory epithelial cells.

Adherence of Mycobacterium avium complex (MAC) to human respiratory epithelial cells (HEp-2) induced 2 distinct modes of internalization. In the first, MAC induced ruffling of HEp-2 cell membrane and formation of surface projections securing the bacilli on the surface, and concurrent membrane depressions, beneath the sites of attachment of bacilli, resulted in internalization of the organisms. The second mode involved formation of membrane folds wrapping around the bacilli, followed by internalization. Two MAC proteins of approximately 31 kD and approximately 25 kD, respectively, were identified that mediated these interactions specific for HEp-2 cells. The N-terminal amino acid sequence of the 31-kD MAC protein displayed homology with the 21-kD hypothetical protein of Mycobacterium tuberculosis, and the 25-kD MAC protein showed homology with Mn-superoxide dismutase of MAC and Mycobacterium leprae. These 2 HEp-2 cell-specific MAC proteins may be involved in the interaction of MAC with epithelial cells.

Amino Acid Sequence↗

PubMed2004

Electrophoretic Mobility of Mycobacterium avium Complex Organisms.

The electrophoretic mobilities (EPMs) of 30 Mycobacterium avium complex organisms were measured. The EPMs of 15 clinical isolates ranged from -1.9 to -5.0 microM cm V(-1) s(-1), and the EPMs of 15 environmental isolates ranged from -1.9 to -4.6 microM cm V(-1) s(-1) at pH 7.

Electrophoresis↗

PubMed2001

Phagocytosis and killing of Mycobacterium avium complex by human neutrophils.

Organisms belonging to the Mycobacterium avium complex (MAC) cause life-threatening bacteremia in immunocompromised patients. Monocytes and macrophages are thought to be responsible for ingestion and killing of MAC. However, it has been suggested that neutrophils may play a role in the early immune response to MAC infection. Here, neutrophils in autologous plasma were incubated (at 0 and 37 degrees C) with M. avium labeled with Auramine O, a potent fluorochrome. Neutrophil phagocytosis was measured by flow cytometry. Neutrophils incubated at 37 degrees C showed an increase in fluorescence over time with a maximum at 15 min, whereas neutrophils on ice showed no time-dependent increase in FL1. At 15 min Fl 1 at 37 degrees C was twice as high as FL1 at 0 degrees C. Examination under the fluorescent microscope showed multiple intracellular fluorescent mycobacteria. Results in nine independent experiments showed time-dependent decrease of colony-forming units in neutrophil-associated live M. avium. Significant killing was observed within 30 min and was complete by 120 min. Observation by electron microscopy clearly confirmed the presence of intraphagosomal MAC, both intact and with evidence of degradation. These data demonstrate that MAC is rapidly phagocytized and killed by human neutrophils. The newly established flow cytometry method should be useful in further studies of neutrophil function and of the role of G-CSF and other cytokines in MAC disease.

Adult↗

PubMed1995

Enhancement of antibiotic susceptibility and suppression of Mycobacterium avium complex growth by poloxamer 331.

The resistance of Mycobacterium avium complex (MAC) to antibiotics is thought to be enhanced by its outer glycolipid layer, which protects the organisms from antibiotics and host defense mechanisms. We hypothesized that surfactants which disrupt the lipid barrier might be of therapeutic value. We evaluated the ability of 10 poloxamer surfactants to inhibit the growth of MAC organisms and to potentiate antimycobacterial drug activity in broth culture using a radiometric assay. Very large, small, or hydrophilic poloxamers had little or no effect. However, certain hydrophobic poloxamers, especially P331, retarded the growth of most isolates of MAC and produced a synergistic effect with rifampin. The MIC of rifampin required to inhibit the growth of MAC was reduced from a mean of 14.6 micrograms/ml (range, 4 to > 32 micrograms/ml) to 1.4 micrograms/ml (range, < 1.125 to 4 micrograms/ml) by 1.0 mg of P331 per ml (P < 0.01). Enhancement of antibiotic susceptibility was observed with concentrations of poloxamer as low as 10 micrograms/ml. These studies suggest that P331 might be useful in increasing the effectiveness of antibiotic therapy of MAC infections.

Anti-Bacterial Agents↗

PubMed1989

[Macrophage respiratory burst-triggering activity of transparent and opaque colonial variants of Mycobacterium avium complex].

The two types of colonial variants of Mycobacterium avium complex, SmT (smooth, transparent, irregular) and SmD (smooth, opaque, dome-shaped) variants, were examined for their triggering activity for macrophage (M phi) respiratory burst, based on chemiluminescence (CL). SmD variants elicited an intense CL from zymosan A-induced M phi s in a dose-dependent manner, although SmT variants induced much lower M phi CL. The M phi s could steadily phagocytose SmT variants, although the phagocytizing rate was considerably lower compared to the case of SmD variants. Treatments of SmD variants with Tween 80, pronase and some endoglycosidases such as alpha-amylase, cellulase, dextranase and pectinase, heating (100 degrees C, 15 min), and delipidation by CHCl3-methanol extraction resulted in a marked reduction in the M phi CL-triggering activity of the SmD variants. Thus, the M phi CL-triggering ligand(s) seems to possess glycolipoprotein-like moieties. Tween 80-treatment of SmT variants, which is known to deprive the polysaccharide outer layer specific to the colonial variants, failed to recover the M phi CL-triggering activity of SmT variants. Therefore, the remarkably reduced M phi CL-triggering ability of the SmT variants may be caused by the extremely lowered expression of the M phi CL-triggering ligands rather than by masking of the CL-triggering ligands by SmT-specific outer layer.

Animals↗

PubMed1997

[Current status in the prevention of Mycobacterium avium complex infections in patients with HIV infection].

Mycobacterium avium complex (MAC) infections in AIDS are increasingly common and contribute to the mortality in severe immunocompromised patients. In this paper, we review the published studies on the prevention of the MAC infections. Rifabutin and the new macrolides (clarithromycin, azithromycin) are shown to be effective in the primary prevention. However, they can fail and are difficult to manage with the antiretroviral treatment, specially antiproteases and prevention of the other opportunistic infections. For the prevention of the relapse of the MAC infections, it is necessary to give a prolonged treatment with a bio-therapy associating at least a new macrolide with rifabutin or ethambutol, which is also difficult to manage with the other treatments.

AIDS-Related Opportunistic Infections↗

PubMed1994

Predictors of survival in patients with AIDS and disseminated Mycobacterium avium complex disease.

Patients with AIDS and disseminated Mycobacterium avium complex disease (DMAC), as defined by the presence of a positive blood culture for MAC, were studied retrospectively to define the natural history of DMAC. All patients had fevers, severe anemia (hematocrit < 26%), or both. Eighty-seven (76%) had signs, symptoms, or laboratory findings related to the gastrointestinal tract, but no distinct syndrome was identified. Sixty-nine patients received antimycobacterial therapy; assignment to therapy was not randomized. In a proportional hazards analysis, shorter survival was associated with higher initial level of mycobacteremia (relative risk [RR], 1.86; 95% confidence interval [CI], 1.49-2.31; P < .001), while administration of antimycobacterial chemotherapy (RR, 0.42; 95% CI, 0.26-0.70; P < .001) and antiretroviral therapy (RR, 0.40; 95% CI, 0.22-0.73; P < .01) had protective effects. Thus, the initial level of mycobacteremia of patients with DMAC may have prognostic value, and administration of antimycobacterial and antiretroviral agents may be associated with prolonged survival.

AIDS-Related Opportunistic Infections↗

PubMed1993

Randomized, placebo-controlled trial of rifampin, ethambutol, and ciprofloxacin for AIDS patients with disseminated Mycobacterium avium complex infection.

Patients with AIDS and disseminated Mycobacterium avium complex (MAC) infection received rifampin (600 mg) plus ethambutol (25 mg/kg) plus ciprofloxacin (750 mg) or matching placebos daily for 8 weeks. Patients were monitored every 2 weeks clinically and by quantitating MAC colony-forming units (cfu) per milliliter of blood. Analysis of baseline characteristics revealed no significant differences between groups. After 8 weeks, MAC cfu had decreased by > or = 1 log/mL in 4 of 9 treated patients versus 0 of 10 placebo recipients while increasing by > or = 1 log/mL in 1 and 7, respectively (P = .006). While the average combined clinical response score declined in both groups, it tended to decrease less in treated patients (P = .36). On the other hand, dose-limiting toxicity (primarily nausea and adverse drug interactions) occurred in 9 of 12 treatment versus 1 of 12 placebo patients (P = .005). Combined rifampin [corrected]-ethambutol-ciprofloxacin therapy for disseminated MAC infection had significant microbiologic efficacy with some evidence of clinical efficacy but was associated with drug intolerance.

AIDS-Related Opportunistic Infections↗

PubMed2006

Increased serum level of vascular endothelial growth factor in Mycobacterium avium complex infection.

OBJECTIVE: Pulmonary infection caused by Mycobacterium avium complex (MAC) is one of the granulomatous diseases which are associated with the expression of vascular endothelial growth factor (VEGF). The aim of the present study was to clarify the association of VEGF with the pathogenesis of MAC infection. METHODOLOGY: The serum VEGF levels in 46 patients with pulmonary MAC infection were compared with those in 16 normal control subjects. Pulmonary lesions were evaluated using chest CT. In 20 patients, after treatment, serum VEGF levels were measured and chest CT performed again to evaluate pulmonary response to treatment. RESULTS: Infected patients had higher serum VEGF levels than controls (435.2 +/- 29.1 vs. 167.0 +/- 10.6 pg/mL, P < 0.0001), and serum VEGF level correlated with the extent of disease. The serum VEGF levels in 14 patients who underwent treatment and exhibited an improvement in their pulmonary lesions decreased significantly compared with the results pretreatment (509.0 +/- 60.7 vs. 303.6 +/- 65.3 pg/mL, P = 0.0092). In infected patients, alveolar macrophages, epithelioid cells and multinucleated giant cells exhibited VEGF overexpression on immunohistochemical staining. CONCLUSIONS: This study suggests that VEGF may be associated with the pathogenesis of pulmonary MAC infection. Additionally, serum VEGF levels may be a useful surrogate marker for evaluating the extent of disease and of the response to treatment.

Adult↗

PubMed1994

Disseminated Mycobacterium avium complex disease in patients with AIDS.

Disseminated Mycobacterium avium complex (MAC) infection is a common complication of advanced HIV disease that is associated with significant morbidity. After diagnosis of MAC by recovery of organisms from blood or other normally sterile sites, specific treatment with multiple-drug regimens is appropriate and may reduce morbidity. Multiple-drug regimens with agents active against MAC should be employed to reduce the development of drug resistance. Unfortunately, as most clinical trials of anti-MAC agents have lasted 12 weeks or less and have not compared specific agents, the most effective multiple-drug regimen has not been established. The U.S. Public Health Service Task Force on Prophylaxis and Therapy of MAC recommends treatment of disseminated disease with at least two antimycobacterial agents, one of which should be clarithromycin or possibly azithromycin. Ethambutol, which may have an additive or synergistic effect in combination with other anti-MAC agents, is a reasonable second drug. Other agents with activity include rifampin or rifabutin, clofazimine, ciprofloxacin, or parenteral amikacin. A microbiological response may require up to 2 to 8 weeks. The clinical response generally parallels the microbiological response. Rifabutin, which is licensed for prophylaxis of MAC, reduces the incidence of and delays the time to MAC bacteremia. Individuals at highest risk of MAC bacteremia (i.e., CD4+ cell counts of < 75-100 cells/microliters) had the most benefit from rifabutin prophylaxis. Tuberculosis must be ruled out before rifabutin prophylaxis is initiated. Careful observation without prophylaxis is an acceptable alternative for those who are not able to take rifabutin or alternative agents.

AIDS-Related Opportunistic Infections↗

PubMed2000

[Development of a case of Mycobacterium avium complex disease from right pleural effusion].

Moist pleurisy in patients with Mycobacterium avium Complex (MAC) is rarer than tuberculosis. We encountered an extremely rare case of MAC disease in a 75-year-old man who initially had only right pleural effusion. Gaffky VII was detected in the pleural effusion, and Mycobacterium avium was identified by culture and PCR. Although administration of antitubercular agents (RFP, INH, EB, and SM) + CAM and thoracic lavage were repeated, the Gaffky persisted strongly. Accordingly, pulmonary decortication and filling of the cavity with an omental flap were performed as surgical treatments. However, fistulas were formed between the remaining empyema cavity and the surgical wounds. Fenestration was also carried out. Postoperatively, centriacinar abnormalities appeared on computed tomography (CT). It has been reported that MAC disease begins with centriacinar abnormalities and the incidence of the lymphatic developmental pattern was low. Tuberculosis (the idiopathic pleuritis type) is considered to be caused this pattern from the primary infection focus. Therefore, the onset of unilateral effusion is extremely rare in patient with MAC disease, suggesting that the lymphatic developmental pattern occurs less frequently in patients with MAC disease. Furthermore, in this case, we speculated that centriacinar abnormalities were the MAC infection foci and could be detected by CT due to surgical invasion.

Aged↗