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PubMed2006

Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease.

RATIONALE: The clinical features and outcome of macrolide-resistant Mycobacterium avium complex (MAC) lung disease are not known. OBJECTIVES: Characterize patients, treatment, and isolates in macrolide-resistant MAC lung disease. METHODS: Retrospective chart review, susceptibility testing, molecular fingerprinting, and DNA sequence analyses of resistant MAC isolates. MEASUREMENTS AND MAIN RESULTS: We identified 51 patients over a 15-yr period with clarithromycin-resistant MAC (minimum inhibitory concentration (MIC)>or=32 microg/ml) lung disease at a single referral center. Twenty-four (47%) patients had nodular disease with bronchiectasis and 27 (53%) had upper lobe cavitary disease. Most patients (77%) had M. intracellulare. Sequencing of the 23S r-RNA gene showed 49 of 51 isolates (96%) with the expected mutation in adenine 2058 or 2059. Risk factors for resistance included macrolide monotherapy or combination with a quinolone only (39/51 or 76%). Macrolide resistance developed in 12 of 303 (4.0%) patients started on the American Thoracic Society-recommended two companion drugs, with no risk difference in clarithromycin versus azithromycin and daily versus intermittent therapy. Sputum conversion with macrolide-resistant MAC occurred in 11 of 14 (79%) patients who received more than 6 mo of injectable aminoglycoside therapy and lung resection, compared with 2 of 37 (5%) who did not. The 1-yr mortality in patients who remained culture positive was 34% (13/38) compared with 0% (0/13) of patients who became culture negative (converted). CONCLUSIONS: Macrolide resistance rarely occurs in patients also receiving ethambutol and a rifamycin. Macrolide-resistant MAC lung disease requires aggressive drug and surgical therapy for cure.

Aged↗

PubMed1995

Distribution of IS901 in strains of Mycobacterium avium complex from swine by using IS901-detecting primers that discriminate between M. avium and Mycobacterium intracellulare.

The presence of the mycobacterial insertion sequence IS901 was studied by PCR with reference strains of Mycobacterium avium complex; 122 veterinary strains of mycobacteria, mainly M. avium complex, isolated from swine; and 15 clinical strains. Four kinds of DNA extraction methods for PCR were compared. Use of the commercial extraction matrix allowed for the faster and easier preparation of PCR-amplifiable DNA than use of NaOH heating extraction or sodium dodecyl sulfate extraction of pretreated mycobacteria. It also provided more effective protection than boiling extraction against the destruction of DNA. Four reference strains of serovars 1 to 3 possessed IS901. Nine reference strains of serovars 1, 4 to 6, 8 to 11, and 21 possessed only IS901 insertion sites. A novel PCR product was found in the other reference strains of serovars 7, 12 to 17, 19, and 20 and two clinical strains of serovar 15. It is suggested that the primers that amplified the insertion portion of IS901 divided the M. avium complex into M. avium, Mycobacterium intracellulare, and other mycobacteria. None of the 110 strains of M. avium complex isolated from swine possessed IS901. It is suggested that the absence of IS901 might be characteristic of swine-derived strains of M. avium complex.

Animals↗

PubMed2005

Discordant molecular characterization results in a Mycobacterium avium complex strain isolated from an AIDS patient.

This report describes an unusual strain of Mycobacterium avium complex isolated from the sputum of an immunocompromised AIDS patient, which did not react with the MAC probe of the BDProbe Tec system, but was identified as Mycobacterium intracellulare by 16S rRNA gene sequencing. Its PCR restriction-enzyme analysis pattern was compatible with an allelic variant of M. avium. It was scotochromogenic, slow-growing and phenotypically identified as Mycobacterium scrofulaceum. Its clinical significance is not certain.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Activity of subinhibitory concentrations of dapsone alone and in combination with cell-wall inhibitors against Mycobacterium avium complex organisms.

MICs of dapsone (p-p'-diaminodiphenylsulfone) were determined radiometrically for ten strains each of the Mycobacterium avium complex (MAC) and Mycobacterium tuberculosis. MICs ranged from 50 to 250 micrograms/ml for Mycobacterium tuberculosis and from 2 to 100 micrograms/ml for MAC. However, at a concentration as low as 1.5 micrograms/ml dapsone significantly inhibited growth of MAC bacteria when used in combination with other drugs specifically acting at the mycobacterial cell-wall level. The latter drugs were used in subinhibitory concentrations, and included m-fluorophenylalanine (an inhibitor of mycoside-C biosynthesis), ethambutol (an inhibitor of arabinogalactan biosynthesis), and ethionamide (an inhibitor of mycolic acid biosynthesis). Using a radiometric method (Bactec 460-TB), the activity of dapsone was found to be enhanced for 2/10 strains in the presence of m-fluorophenylalanine, for 3/10 strains in the presence of ethambutol and for 5/10 strains in the presence of ethionamide. A satisfactory correlation between the radiometric data and bacterial viable counts was established.

Cell Wall↗

PubMed2006

Early pulmonary resection for Mycobacterium avium complex lung disease treated with macrolides and quinolones.

BACKGROUND: The purpose of this study was to examine the postoperative outcomes of patients with Mycobacterium avium complex (MAC) lung lesions persisting despite treatment with multiple antibiotics. METHODS: Patients with localized pulmonary lesions persisting despite extensive state-of-the art antimicrobial chemotherapy became candidates for surgical resection. Twenty-two patients who were expected to retain sufficient postoperative pulmonary function were included in this study. These patients received chemotherapy for 2 to 37 months (mean, 17). Surgical procedures were lobectomy (n = 15), segmentectomy (n = 4), and partial lung resection (n = 6). Three patients underwent bilateral resections. RESULTS: Mycobacterium avium complex causing bronchiectasis or cavitary lesions was detected preoperatively in all 22 patients. There was no major operative morbidity or mortality. Postoperative chemotherapy was continued for 6 to 35 months. All patients were alive and well at follow-ups ranging from 6 to 164 months (median, 46). Both vital capacity and forced expiratory volume in 1 second after surgery were maintained at 89% and 84% of the preoperative values, respectively. Mycobacterium avium complex disappeared from sputum after surgery in all patients. In 1 patient, 4 months after resection of a cavitary lesion, MAC-positive sputum presumed to be from the contralateral lung lesion became negative during continuation of chemotherapy. CONCLUSIONS: The long-term outcomes of patients operated on for MAC resistant to antimicrobial chemotherapy were excellent. For such patients, we recommend surgery before the disease becomes exceedingly advanced and nonresectable. Additionally, in extensive disease, the excision of large cavitary bacterial foci may assist the medical management of contralateral lesions.

Adult↗

PubMedDate not supplied

CT features of pulmonary Mycobacterium avium complex infection.

OBJECTIVE: The purposes of this study were to describe and compare the prevalence of disease features in subjects with Mycobacterium avium complex (MAC) disease with those of Mycobacterium tuberculosis infection (MTB), to compare the abilities of CT and chest radiography to identify the features of MAC disease, and to determine if sputum positivity is related to any of the CT features of MAC disease. METHODS: Computed tomographic scans of 15 subjects with MTB and 55 subjects with MAC were reviewed by 2 observers. Sputum culture results (obtained within 1.9 +/- 2.8 days of scanning) were available in 50 of the 55 subjects with MAC. RESULTS: Bronchiectasis involving four or more lobes (often associated with centrilobular nodules) was seen only in subjects with MAC. The combination of right middle lobe and lingular bronchiectasis was seen only in MAC (p = 0.015). Thirty-one of the 34 subjects (91%) with MAC who had cavities on CT had a positive sputum culture within 3 weeks of CT, compared with 7 of 12 subjects (58%) without cavities (p = 0.001). Similarly, 36 of 42 subjects (85%) with airspace disease, but only 2 of 8 subjects (25%) without airspace disease grew mycobacteria from their sputa (p < 0.001). Sputum positivity was not associated with the presence of bronchiectasis (p = 0.156) or nodules (p = 0.377). CONCLUSION: A subgroup of patients with MAC may be distinguished from those with MTB by the presence of widespread bronchiectasis, particularly if it involves the right middle lobe and lingula. Cavities and airspace opacification on CT are associated with positive sputum cultures for MAC.

Female↗

PubMed1993

Identification of Mycobacterium avium complex strains belonging to serovars 21-28 by three commercial DNA probe tests.

Various reference strains of Mycobacterium avium complex (MAC) belonging to serovars 21-28 were identified by three DNA probe tests, i.e., Gen-Probe, AccuProbe and SNAP tests. All of these DNA probe tests were in agreement for strains identified as M. avium or M. intracellulare. The tested serovar strains involved M. avium, M. intracellulare, MAC reactive only with Probe X of SNAP test ('Probe X-reactive MAC'), M. scrofulaceum reactive with Probe X of SNAP test ('Probe X-reactive M. scrofulaceum'), and typical M. scrofulaceum which did not react with any of the probes. Both reference strains belonging to serovar 21 were M. avium, and none of the other serovars included this species. On the contrary, M. intracellulare was found in serovars 22, 25, 26, and 28. 'Probe X-reactive MAC' were also widely found in serovars 23, 24, 26, 27, and 28, while 'Probe X-reactive M. scrofulaceum' was seen only in serovar 22. These results confirm the usefulness of SNAP test to identify the MAC showing no reactivity to Gen-Probe and AccuProbe.

DNA Probes↗

PubMed1998

Susceptibilities of Mycobacterium tuberculosis and Mycobacterium avium complex to lipophilic deazapteridine derivatives, inhibitors of dihydrofolate reductase.

Twelve lipophilic 2,4-diamino-5-methyl-5-deazapteridine derivatives and trimethoprim were evaluated for activity against Mycobacterium tuberculosis and Mycobacterium avium in vitro. Six of the compounds had MICs of < or =12.8 mg/L and < or =1.28 mg/L against M. tuberculosis and M. avium, respectively; trimethoprim MICs were >128 mg/L and >12.8 but < or =128 mg/L, respectively. Two compounds, with either a 2-methyl-5-methoxy phenyl or 2-methoxy-5-trifluoromethyl phenyl linked at the 6-position of the deazapteridine moiety by a CH2NH bridge, had MICs of < or =0.13 mg/L against M. avium; the two compounds also had apparent I50 values for dihydrofolate reductase of 2 and 8 nM, respectively, compared with an I50 of 400 nM with trimethoprim. Four of the compounds were selectively toxic to mycobacteria as compared with Vero cells. These results demonstrated that lipophilic antifolates can be synthesized which are more active against mycobacteria than trimethoprim and which possess selective toxicity.

Animals↗

PubMed1994

Low-dose dexamethasone as adjunctive therapy for disseminated Mycobacterium avium complex infections in AIDS patients.

Five human immunodeficiency virus-infected patients with disseminated Mycobacterium avium complex infection had progressive weight loss and persistent fever despite multidrug antimycobacterial therapy. These patients were given daily low-dose oral dexamethasone (typically 2 mg/day) as adjunctive therapy. All had substantial and sustained weight gain (12 to 50% of pre-steroid treatment body weight [P < 0.03]), reduction in fever, and an improved sense of well-being. The serum albumin level increased during dexamethasone therapy (from 3.06 +/- 0.59 g/dl [mean +/- standard deviation] to 3.9 +/- 0.22 g/dl [P < 0.01]), while the serum alkaline phosphatase level fell (from 368 +/- 247 U/liter to 128 +/- 43.6 U/liter [P < 0.04]). Further studies of the potential role for corticosteroids in the management of disseminated M. avium complex infections in human immunodeficiency virus-infected patients are warranted.

AIDS-Related Opportunistic Infections↗

PubMed1994

Bacteriostatic and bactericidal activities of paromomycin against Mycobacterium avium complex isolates.

The MICs and MBCs of paromomycin for 32 Mycobacterium avium complex (MAC) strains isolated from patients with the acquired immunodeficiency syndrome were determined by a radiometric broth dilution method. The MICs for the majority of strains were either 8 or 16 mg/L and the MBCs were four- to eight-fold higher. Paromomycin merits further evaluation as oral prophylaxis against disseminated MAC infection.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Treatment of Mycobacterium avium complex immune reconstitution disease in HIV-1-infected individuals.

Immune reconstitution disease caused by Mycobacterium avium complex (MAC) infection presenting shortly after the introduction of highly active antiretroviral therapy (HAART) has been reported with increasing frequency in persons with HIV-1 infection during the past several years. Several therapeutic modalities have been utilized for this entity, but the optimal means of treating MAC immune reconstitution disease remains unclear. We now describe a patient who underwent some of these therapies. We then review the therapeutic outcomes from the numerous case reports of this disorder. Finally, we propose recommendations and a clinical algorithm regarding the optimal means of treatment of MAC immune reconstitution disease during HIV-1 infection.

AIDS-Related Opportunistic Infections↗

PubMed1996

Disseminated Mycobacterium avium complex: correlation between blood and tissue burden.

To determine the relationship between levels of Mycobacterium avium complex (MAC) in blood and tissues, histopathologic examination and quantitative MAC cultures were done on blood samples and tissue samples of 7 organs at autopsy of 10 AIDS patients who had been treated for MAC bacteremia. Blood and tissue cultures were negative for MAC for 3 of the patients and positive for 7. The numbers of MAC colony-forming units in the blood and tissues were highly correlated. The highest concentrations of MAC were observed in the reticuloendothelial organs, with a maximum of 6.9 log10 cfu/g in mesenteric lymph nodes and 6.8 log10 cfu/g in spleen. Histopathologic findings paralleled quantitative cultures and were consistent with entry of MAC via lymphatics through the gastrointestinal tract, followed by hematogenous dissemination.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Effect of Tween 80 on the growth of Mycobacterium avium complex.

The effect of Tween 80 on the growth of Mycobacterium avium complex (MAC) in liquid culture condition was investigated. Observation of the colony-forming units (CFU) and the morphology of MAC with transmission and scanning electron microscopy showed that Tween 80 at 0.05% in the medium (ca. 0.5 mg/ml) had bacteriostatic action and caused cell elongation. Tween 80 at 0.5% or more in the medium (ca. 5 mg/ml) reduced the quantity of MAC glycolipids and also led to false positive or positive results in biochemical tests for mycobacterial identification using nitrate reductase, urease, or arylsulfatase. To determine whether or not surfactants could reduce the MAC permeability barrier, the minimal inhibitory concentration (MIC) of antituberculosis drugs on MAC was determined in liquid medium with or without several kinds of surfactants including Tween 80. Five surfactants including Tween 80 increased the activity of antituberculosis drugs to MAC. These findings suggest that Tween 80 acts directly on the cell wall of MAC.

Antitubercular Agents↗

PubMed2005

Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium complex lung disease.

Ethambutol (EMB) is an important component of multidrug treatment regimens for Mycobacterium avium complex lung disease. Ocular toxicity is the most important potential EMB toxicity, especially in the elderly population with M. avium complex lung disease. Two hundred twenty-nine patients with M. avium complex lung disease, 55% women and 53% with nodular/bronchiectatic disease, received a mean of 16.1 +/- 10.8 months of multidrug therapy that included EMB. Fifty patients (22%) were known to have preexisting ocular disease. While on EMB, 97 (42%) patients consulted an opthalmologist and 24 (10%) stopped EMB at least temporarily. Eight of 139 patients (6%) on daily therapy were diagnosed with EMB ocular toxicity, whereas 0 of 90 patients on intermittent therapy had EMB ocular toxicity (p = 0.05). All patients with EMB ocular toxicity developed symptoms between outpatient clinic appointments; none were diagnosed with routine visual acuity and color vision testing. All patients with EMB ocular disease returned to baseline ocular status after discontinuation of EMB. Intermittent EBM administration was associated with less ocular toxicity than daily EMB administration in this patient population.

Aged↗

PubMed1995

Allogeneic BMT in a patient with CML and prior disseminated infection by mycobacterium avium complex.

A patient with chronic myeloid leukemia (CML) who developed a disseminated infection by mycobacterium avium complex (MAC) was successfully treated with rifampin, ethambutol, isoniazid, cycloserin and ciprofloxacin. Diagnosis was proven by histologic examination of hepatic biopsy and culture of the liver biopsy material. Two years later the patient underwent allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor. Antimycobacterial prophylaxis to MAC with ethambutol, cycloserin and ciprofloxacin was given throughout the immediate post-transplant period. On day +25 post-BMT secondary prophylaxis was changed to ciprofloxacin and clarithromycin due to hepatic toxicity. Treatment was maintained until day 100 without side effects. There was no evidence of recurrent mycobacteriosis. Eight months after BMT the patient is well, with a good performance status and chronic graft-versus-host disease (GVHD) limited to the oral mucosa. Thus, MAC infection prior to transplant need not be a contraindication to successful BMT.

Adult↗

PubMed2001

Azithromycin prophylaxis for Mycobacterium avium complex during the era of highly active antiretroviral therapy: evaluation of a provincial program.

Mycobacterium avium complex (MAC) disease was evaluated in a provincial program of azithromycin prophylaxis. Highly active antiretroviral therapy (HAART) was prescribed to 383 (65%) of 587 patients eligible for MAC prophylaxis (CD4 <75 cells/mm3). By use of an intent-to-treat analysis, MAC disease was observed in 21 of 271 patients who did not receive prophylaxis (incidence rate, 8 events per 100 person-years). MAC events occurred in 10 of 316 patients who received azithromycin (2.37 events per 100 person-years). Localized lymphadenitis compatible with immune reconstitution disease accounted for 23% of all MAC events, in contrast to studies in the pre-HAART era, where almost all cases were disseminated. None of the MAC isolates from the 10 prophylaxis failures were resistant to azithromycin. Azithromycin appeared to be protective against disseminated MAC in patients who were either unresponsive or nonadherent to HAART, but it did not prevent the development of immune reconstitution disease due to MAC.

AIDS-Related Opportunistic Infections↗

PubMed2000

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.

Adult↗

PubMed1992

Nonopsonic uptake of Mycobacterium avium complex by human monocytes and alveolar macrophages.

The uptake of Mycobacterium avium complex (MAC) microorganisms by human peripheral blood monocytes (PBMs) and alveolar macrophages (AMs) is not well understood. We have previously shown, under opsonic conditions, that humoral factors are important in mediating the uptake of MAC by PBMs. However, the receptor-ligand interactions occurring under nonopsonic conditions remain unclear. We compared the uptake of untreated human PBMs and AMs in a serum-free medium with phagocytes treated to remove surface receptors. Removal of complement receptors CR1 and CR3, the Fc receptor (FcR), and the transferrin receptor (TfR) resulted in significantly lower levels of MAC uptake in serum-free medium by both PBMs and AMs. The addition of barley beta-glucan or mannan from Saccharomyces cerevisiae inhibited MAC uptake by untreated phagocytes in a dose-dependent manner. MAC uptake by PBMs or AMs was never completely abrogated by combining treatments (removal of CR1, CR3, FcR, and TfR and adding mannan or beta-glucan), indicating still-unknown mechanisms of uptake under nonopsonic conditions. We conclude that CR1, CR3, FcR, TfR, the mannose receptor, and possibly a separate beta-glucan-inhibitable receptor all may be involved in nonopsonic uptake of MAC by both PBMs and AMs.

Cells, Cultured↗