Differential virulence of Mycobacterium avium strains isolated from HIV-infected patients with disseminated M. avium complex disease

The role that colonization with Mycobacterium avium plays in the development of disseminated disease is unclear. In this study, we determined whether all M. avium strains isolated from the portals of M. avium infection are capable of crossing the mucosal border and causing infection. The patients in this study were enrolled in AIDS Clinical Trial Group protocol 341. The patients were divided into 3 groups; 2 groups differed in their immunological and clinical risk for M. avium disease. A third group (n=22 patients) had culture-documented disseminated M. avium complex disease at the time of entry in the study. Eight of 22 patients had M. avium isolated from both a colonized site and blood or bone marrow specimens. All 8 patients had distinct M. avium strains; 2 patients had a polyclonal infection. The virulence properties of 13 strains were determined, including invasion of gastrointestinal cells and replication in macrophages. There were significant differences in the virulence properties, and these differences may provide insight into the interplay between microbial pathogenesis and host defense.     

Characterization of Mycobacterium avium complex related mycobacteria isolated from an African environment and patients with AIDS

Thirteen isolates from African AIDS patients and from the environment in Zaire were identified as members of the Mycobacterium avium complex by phenotypic tests. RFLP analysis showed that the isolates belong to a genetically homogeneous cluster. The 16S rRNA sequence analysis suggests a close relationship with the P‐49 strain (ATCC 35847), a reference strain for the serotype 7 of M. avium complex. This work shows the close relationship between certain M. avium complex strains responsible for disseminated infection in AIDS patients and M. avium complex strains isolated from the environment in Zaire. Further, our findings confirm that atypical mycobacteria may disseminate in AIDS patients in Africa and suggest that infection in these patients probably originates in their environment.     

Successful short-term suppression of clarithromycin-resistant Mycobacterium avium complex bacteremia in AIDS. California Collaborative Treatment Group.

During a randomized study of clarithromycin plus clofazimine with or without ethambutol in patients with AIDS and Mycobacterium avium complex (MAC) bacteremia, eight participants received additional antimycobacterial drugs following the detection of a clarithromycin-resistant isolate (MIC, > 8 micrograms/mL). A macrolide (seven received clarithromycin, one azithromycin) and clofazimine were continued; additional treatment included various combinations of ethambutol, ciprofloxacin, amikacin, and rifabutin. After the detection of a resistant isolate and before receipt of additional antimycobacterials, the median peak MAC colony count in blood was 105 cfu/mL (range, 8-81,500 cfu/mL). After additional antimycobacterials, the median nadir MAC colony count was 5 cfu/mL (range, 0-110 cfu/mL). Five (63%) of eight patients had a > or = 1 log10 decrease, including two who achieved negative blood cultures; all of these responses occurred in patients originally assigned to clarithromycin plus clofazimine. Treatment of clarithromycin-resistant MAC bacteremia that emerges during clarithromycin-based treatment can decrease levels of bacteremia and transiently sterilize blood cultures.     

Pathogenicities of Mycobacterium intracellulare and M. avium strains to the mice which were isolated from non-tuberculous mycobactriosis patients

The virulence of 5 strains of M. intracellulare and 6 strains of M. avium to mice were examined. The former bacteria were obtained from the patients with mycobacterial pulmonary disease and the latter were from AIDS patients respectively. C57BL/6 (NRAMP-1 susceptible) and its NRAMP-1 congenic mice (resistant) were used to evaluate the virulence of these bacteria. Three of the 5 strains of M. intracelllulare showed a relatively high virulence. They grew in the liver, spleen and lungs of susceptible mice and even in the lungs of resistant mice. On the other hand, none of 6 strains of M. avium could grow in either susceptible or resistant mice. In conclusion, our mouse model may be a useful tool for evaluating the virulence of bacteria isolated from mycobacteriosis patients.     

Comparison of antituberculosis drug regimens for lung disease caused by Mycobacterium avium complex

A total of 123 patients with moderately advanced, cavitary lung disease caused by Mycobacterium avium complex untreated previously received different regimens of antituberculosis agents. The rate of sputum conversion (continuously negative cultures for six months or more) was compared among the regimens. It was shown that the regimens of rifampin + isoniazid + streptomycin and rifampin + isoniazid + enviomycin were superior to the regimens of streptomycin + isoniazid + p-aminosalicylate, isoniazid alone or isoniazid + p-aminosalicylate. This finding demonstrated that the regimens including rifampin, isoniazid and streptomycin or enviomycin were really effective in the initial treatment of lung disease caused by M avium complex.     

Outcome of pulmonary Mycobacterium avium complex (MAC) disease treated with clarithromycin (CAM)-containing regimens]

We retrospectively investigated the efficacy of regimens including clarithromycin (CAM) in 129 patients with Mycobacterium avium complex (MAC) pulmonary disease and their outcomes. None of the patients suffered from acquired immunodeficiency syndrome. All were observed for over 12 months. We studied the factors that may affect sputum conversion and fatal outcomes by logistic regression analysis. The results indicated that the presence of either cavitation or bronchiectasis was significantly correlated with persistent MAC-positive culture results in sputum (Odds ratio, 4.71, 95%; CL, 1.21-18.5; P<0.05). Regimens including antituberculous drugs and CAM were administered to 118 patients, 11 of whom received CAM alone because of the adverse events of antituberculous agents. There was no difference in sputum conversion or mortality between the two groups, suggesting that the pattern of drug combination should be further investigated.     

Comparative antigenic analysis of Mycobacterium avium complex (MAC) isolates from AIDS patients.

Sonicates of several Mycobacterium avium complex (MAC) strains isolated from acquired immunodeficiency syndrome (AIDS) patients were characterized in order to study the prominent antigens of these strains. Sonicates of 6-week-old cultures were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. A major 12 kDa glycoprotein antigen was observed in all the sonicates along with other proteins ranging up to 100 kDa. Western blotting, using the 12 kDa M. leprae 'specific' murine monoclonal antibody (MAb) MLO6, indicated the presence of a determinant in the 12 kDa antigen (in all the MAC isolates studied) which was immunologically cross-reactive with the 12 kDa antigen of M. leprae. The transparent variant of MAC 101 also demonstrated MLO6 reactivity while the opaque variant did not. Polyclonal antiserum raised against MAC 101 sonicate reacted with all the MAC isolates in immunodiffusion. These observations point to the cross-reactivity between these strains and suggest that they possess a M. leprae 'specific' determinant on a cross-reacting component which could be involved in virulence.     

Comparison of azithromycin and clarithromycin in triple therapy regimens for the eradication of Helicobacter pylori

OBJECTIVE: We sought to compare an azithromycin-based regimen with an already established clarithromycin-based regimen in the eradication of Helicobacter pylori infection. METHODS: A prospective, randomized, blinded comparative analysis was performed on 56 patients with upper GI symptoms who presented to the Gastroenterology Department at the Naval Medical Center Portsmouth. All patients had documented H. pylori infection on endoscopy via rapid urease test and histopathology. Patients were randomized to a treatment arm, which consisted of bismuth, clarithromycin, amoxicillin, and lansoprazole (B-LAC) or one consisting of bismuth, azithromycin, amoxicillin, and lansoprazole (B-LAA). To assess eradication, patients then received repeat endoscopy at 8 wk from entrance into the study. Rapid urease test and histopathology were again used to evaluate infection. Patients recorded all side effects. Comparison between the two groups was made using the chi2 method. RESULTS: Of the 56 patients included in the study, 27 went on to receive B-LAC, whereas 29 received B-LAA. The per protocol eradication rate was 84.6% with B-LAC and 55.5% with B-LAA (p = 0.021). Under intention to treat analysis, the eradication rates for B-LAC and B-LAA were 81% and 52%, respectively (p = 0.019). There was a significant difference between the two groups in number of subjects using nonsteroidal anti-inflammatory drugs (NSAIDs) (p = 0.013) and a trend toward a difference in histamine-2 (H2) blocker use (p = 0.066). Taking these two variables into account, a logistical regression was performed and continued to show a significant superiority in the B-LAC regimen (p = 0.03). CONCLUSIONS: The results of our study suggest that B-LAC is superior to B-LAA in the eradication of Helicobacter pylori. Our results also suggest that B-LAA is not a suitable regimen in the treatment of H. pylori because of its substandard eradication rate.     

Related strains of Mycobacterium avium cause disease in children with AIDS and in children with lymphadenitis

Sequence analysis of the ribosomal internal transcribed spacer of 56 Mycobacterium avium complex isolates from pediatric patients with AIDS or lymphadenitis revealed (similar to the situation in adults) that the closely related Mav-B and Mav-A sequevars caused the vast majority of disease. IS1245 restriction fragment-polymorphism analysis and pulsed-field gel electrophoresis revealed sets of isolates with closely related patterns among strains from patients in the Boston area and among isolates from Los Angeles and Miami patients. The finding of related strains that cause disease in epidemiologically unrelated patients is most consistent with one of two hypotheses: (1) a limited subset of M. avium strains is more virulent and therefore more likely to cause disease in humans, or (2) pathogenic strains are more prevalent in the environment.     

A prospective randomized trial of four three-drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: excess mortality associated with high-dose clarithromycin. Terry Beirn Community Programs for Clinical Research on AIDS.

The optimal regimen for treatment of Mycobacterium avium complex (MAC) disease has not been established. Eighty-five AIDS patients with disseminated MAC disease were randomized to receive a three-drug regimen of clarithromycin, rifabutin or clofazimine, and ethambutol. Two dosages of clarithromycin, 500 or 1,000 mg twice daily (b.i.d.), were compared. The Data and Safety Monitoring Board recommended discontinuation of the clarithromycin dosage comparison and continuation of the rifabutin vs. clofazimine comparison. After a mean follow-up of 4.5 months, 10 (22%) of 45 patients receiving clarithromycin at 500 mg b.i.d. had died (70 deaths per 100 person-years) compared with 17 (43%) of 40 patients receiving clarithromycin at 1,000 mg b.i.d. (158 deaths per 100 person-years) (relative risk, 2.43; 95% confidence interval, 1.11-5.34; P = .02). After 10.4 months, 20 (49%) of 41 patients receiving rifabutin had died (81 deaths per 100 person-years) compared with 23 (52%) of 44 patients receiving clofazimine (94 deaths per 100 person-years) (relative risk, 1.20; 95% confidence interval, 0.65-2.19; P = .56). Bacteriologic outcomes were similar among treatment groups. In treating MAC disease in AIDS patients, the maximum dose of clarithromycin should be 500 mg b.i.d.     

Impact of highly active antiretroviral therapy on onset of Mycobacterium avium complex infection and cytomegalovirus disease in patients with AIDS

OBJECTIVES: To assess the impact of highly active antiretroviral therapy (HAART) on the onset of first disseminated Mycobacterium avium complex (MAC) infection and first cytomegalovirus (CMV) disease episode in HIV-infected at-risk patients. METHODS: The incidence of the two infections occurring in at-risk patients was calculated for two periods (January 1995-June 1996 and July 1996-December 1997) using the database of the HIV-infected patients followed in the Infectious Diseases Department at the Pitié-Salpêtrière Hospital in Paris. HAART was progressively introduced in late June 1996 in France. RESULTS: A total of 91 first disseminated MAC infections and 124 first CMV disease episodes were recorded. The incidence of first disseminated MAC infections fell from 13.4 per 100 person-years in the first 18-month period to 2.6 per 100 person-years in the second 18-month period. Similarly, the incidence of first CMV disease episodes fell from 20.9 to 3.5 per 100 person-years. Fourteen patients on HAART developed a first MAC infection, 12 (85.7%) within 2 months of starting HAART. Nineteen patients on HAART had a first CMV disease episode, 10 (52.6%) within 2 months of starting HAART. CONCLUSIONS: HAART led to a five-fold decrease in the incidence of first disseminated MAC infections and a six-fold decrease in first CMV disease episodes, although patients remain vulnerable to both diseases for approximately 2 months after starting HAART.     

Prevalence of Mycobacterium avium complex in respiratory specimens from AIDS and non-AIDS patients in a San Francisco hospital

Over the past several years there has been a large increase in the recovery of Mycobacterium avium complex (MAC) isolates from respiratory specimens submitted to the clinical laboratory at San Francisco General Hospital (SFGH). This increase in MAC recovery correlates with an increase in the number of cases of acquired immunodeficiency syndrome (AIDS) in the community. Although it is well known that MAC is often isolated from patients with AIDS, the isolation of MAC from respiratory specimens is often attributed to contamination of the specimen with MAC organisms present in the environment. To determine whether the increase in MAC isolates recovered at SFGH was due to an increase in environmental contamination of specimens or to the increase in our AIDS patient population, we conducted a study of the prevalence of MAC in respiratory specimens from AIDS versus non-AIDS patients. Results of specimens submitted to the clinical laboratory at SFGH for culture of mycobacteria were reviewed over a 12-yr period, from 1977 through 1988. The prevalence of MAC in respiratory specimens from AIDS and non-AIDS patients was determined for 4 yr during this period: the pre-AIDS year 1977; the first year AIDS was reported in San Francisco, 1981; 1984; and 1987. In 1977 and 1981 the prevalence of MAC in respiratory specimens was less than or equal to 0.5%, and all MAC isolates were recovered from non-AIDS patients. In 1984 the prevalence of MAC in respiratory specimens for AIDS and non-AIDS patients was 6.5 and 0.3%, respectively, and in 1987, 8.8 and 0.3%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Killing of Mycobacterium avium by neutrophils and monocytes from AIDS patients treated with recombinant granulocyte-macrophage colony-stimulating factor.

In this study, 30 AIDS patients without Mycobacterium avium infection were randomized to receive treatment with azithromycin (1200 mg), granulocyte-monocyte colony-stimulating factor (GM-CSF; 250 microg/m2/day for 5 days), or both agents. The M. avium killing capacity of neutrophils and monocytes harvested from each patient before intervention and during (day 4), and after therapy (day 8) was assessed. The mean virus load change in the groups receiving GM-CSF was +0.14 log human immunodeficiency virus RNA. After GM-CSF therapy, neither neutrophils nor monocytes could significantly reduce M. avium growth (P=.96 and.31, respectively). Bone pain, myalgia, presyncope, or fever occurred in 55% of patients receiving GM-CSF. Thus, the GM-CSF regimen used in this study did not affect virus load, frequently caused adverse reactions, and did not improve the M. avium killing capacity of neutrophils and monocytes. Future studies using a different GM-CSF regimen are indicated.     

AIDS病人真菌菌种分离鉴定及体外抗真菌药敏分析

目的了解新疆地区艾滋病(AIDS)病人真菌感染的菌种分布和优势菌株,并检测AIDS病人病原真菌对不同抗真菌药物的体外敏感性,为临床早期诊断及合理用药提供科学依据,并发现该地区的耐药情况。方法分别取AIDS病人口咽、呼吸道、消化道及泌尿、生殖道的标本,采用常规方法做真菌培养,用科玛嘉显色培养基进行鉴定,药敏试验采用ATBTMFUNGUS3试剂盒测定50株分离酵母菌对5-氟胞嘧啶、两性霉素B、氟康唑、伊曲康唑、伏立康唑的体外敏感性。结果100株分离菌株中,念珠菌属为97株,其他菌属3株;其中白念珠菌85株,克柔念珠菌6株,热带念珠菌2株,光滑念珠菌1株。曲霉菌属2株,分别为烟曲霉和土曲霉;接合菌属1株,为根霉。结论新疆地区AIDS病人真菌感染仍以白念珠菌为优势菌种,并有罕见菌种出现。抗真菌药物以5-氟胞嘧啶、两性霉素B敏感性较高,而唑类存在不同程度的耐药。     

A case of pneumonia caused by Mycobacterium avium complex successfully treated with clarithromycin

We reported on a 79-year-old woman with pneumonia caused by Mycobacterium avium complex (MAC). She was admitted with fever, general fatigue, and cough. A chest X-ray film showed infiltrative shadows in the right lung field. In spite of administration of conventional antibiotics, the infiltrative shadows enlarged. A chest CT scan revealed areas of consolidation and ground glass opacities. Bronchoalveolar lavage (BAL) examination revealed an increased number of lymphocytes. Transbronchial lung biopsy revealed many granulomatous regions with giant cells. Mycobacterium intracellulare was found in the culture of BAL fluid and identified by PCR. Treatment was started with rifampicin, ethambutol, and clarithromycin. However, rifampicin and ethambutol were soon discontinued because of severe anorexia. Her symptoms and the radiographic appearance markedly improved following treatment of clarithromycin alone. Subsequently small doses of rifampicin and ethambutol were restarted because her general condition was much improved. These findings suggest that clarithromycin is an effective and tolerable agent for elderly patients with MAC.