Gwen A. Huitt

Clinical Significance of Differentiation of Mycobacterium massiliense from Mycobacterium abscessus

RATIONALE Mycobacterium massiliense has been recognized as a separate species from Mycobacterium abscessus; however, little is known regarding the clinical impact of this differentiation. OBJECTIVES To compare clinical features and treatment outcomes between patients with M. abscessus lung disease and those with M. massiliense lung disease. METHODS We performed molecular identification of stored clinical isolates of M. abscessus complex and compared clinical characteristics and treatment outcomes between 64 patients with M. abscessus lung disease and 81 patients with M. massiliense lung disease. MEASUREMENTS AND MAIN RESULTS The clinical and radiographic manifestations of disease caused by each species were similar. Standardized combination antibiotic therapy, including a clarithromycin-containing regimen in combination with an initial 4-week course of cefoxitin and amikacin, was given to 57 patients (24 with M. abscessus and 33 with M. massiliense) for more than 12 months. The proportion of patients with sputum conversion and maintenance of negative sputum cultures was higher in patients with M. massiliense infection (88%) than in those with M. abscessus infection (25%; P < 0.001). Inducible resistance to clarithromycin (minimal inhibitory concentrations ≥ 32 μg/ml) was found in all tested M. abscessus isolates (n = 19), but in none of the M. massiliense isolates (n = 28). CONCLUSIONS Treatment response rates to combination antibiotic therapy including clarithromycin were much higher in patients with M. massiliense lung disease than in those with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of clarithromycin-containing antibiotic therapy against M. abscessus lung disease.

Clinical and Microbiologic Outcomes in Patients Receiving Treatment for Mycobacterium abscessus Pulmonary Disease

BACKGROUND Mycobacterium abscessus can produce a chronic pulmonary infection for which little is known regarding optimal treatment and long-term outcomes. METHODS We performed a retrospective observational study (2001-2008) including all patients who met American Thoracic Society criteria for M. abscessus pulmonary disease. Our aim was the evaluation of clinical and microbiologic outcomes in patients treated with combined antibiotic and surgical therapy, compared with antibiotic therapy alone. RESULTS A total of 107 patients were included in the analysis. Patients were predominantly female (83%) and never-smokers (60%), with a mean age of 60 years. Fifty-nine (55%) of 107 patients had coexistent or previous history of Mycobacterium avium complex pulmonary infection. High-resolution chest CT showed bronchiectasis and nodular opacities in 98% of patients and cavities in 44%. Sixty-nine (46 medical, 23 surgical) patients were followed up for a mean duration of 34 months (standard deviation, 21.1 months, range, 2-82 months). Cough, sputum production, and fatigue remained stable, improved, or resolved in 80%, 69%, and 59% of patients, respectively. Twenty (29%) of 69 patients remained culture positive, 16 (23%) converted but experienced relapse, 33 (48%) converted to negative and did not experience relapse, and 17 (16%) died during the study period. There were significantly more surgical patients than medical patients whose culture converted and remained negative for at least 1 year (57% vs 28%; P = .022). CONCLUSIONS Patients with M. abscessus pulmonary disease who are treated with multidrug antibiotic therapy and surgery or antibiotic therapy alone had similar clinical outcomes. However, surgical resection, in addition to antibiotics, may offer a prolonged microbiologic response.

Aminoglycoside Toxicity: Daily versus Thrice-Weekly Dosing for Treatment of Mycobacterial Diseases

Aminoglycoside use is limited by ototoxicity and nephrotoxicity. This study compared the incidences of toxicities associated with 2 recommended dosing regimens. Eighty-seven patients with tuberculosis or nontuberculous mycobacterial infections were prospectively randomized by drug to receive 15 mg/kg per day or 25 mg/kg 3 times per week of intravenous streptomycin, kanamycin, or amikacin. Doses were adjusted to achieve target serum concentrations. The size of the dosage and the frequency of administration were not associated with the incidences of ototoxicity (hearing loss determined by audiogram), vestibular toxicity (determined by the findings of a physical examination), or nephrotoxicity (determined by elevated serum creatinine levels). Risk of ototoxicity (found in 32 [37%] of the patients) was associated with older age and with a larger cumulative dose received. Vestibular toxicity (found in 8 [9%] of the patients) usually resolved, and nephrotoxicity (found in 13 [15%] of the patients) was mild and reversible in all cases. Subjective changes in hearing or balance did not correlate with objective findings. Streptomycin, kanamycin, and amikacin can be administered either daily or 3 times weekly without affecting the likelihood of toxicity.

Effects of Gender and Age at Diagnosis on Disease Progression in Long-term Survivors of Cystic Fibrosis

RATIONALE Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts. OBJECTIVES Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF. METHODS Retrospective analysis of the Colorado CF Database (1992-2008), CF Foundation Registry (1992-2007), and Multiple Cause of Death Index (1992-2005). MEASUREMENTS AND MAIN RESULTS Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV(1) decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV(1) declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV(1) decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV(1) improvement in response to CF center care. CONCLUSIONS For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.

Alpha-1-antitrypsin (AAT) anomalies are associated with lung disease due to rapidly growing mycobacteria and AAT inhibits Mycobacterium abscessus infection of macrophages

Rapidly growing mycobacteria (RGM) are ubiquitous in the environment but cause lung disease in only a fraction of exposed individuals. This variable susceptibility to disease implies vulnerability to RGM infection due to weakness in host defense. Since most persons who contract RGM lung disease have no known host defense defect, it is likely that uncharacterized host deficiencies exist that predispose to RGM infection. Alpha-1-antitrypsin (AAT) is a host factor that may protect individuals from respiratory infections. Therefore, we assessed AAT protein anomalies as a risk factor for RGM lung disease. In a cohort of 100 patients with RGM lung disease, Mycobacterium (M.) abscessus was the most prevalent organism, isolated in 64 (64%) subjects. Anomalous AAT proteins were present in 27% of the cohort, which is 1.6 times the estimated prevalence of anomalous AAT proteins in the United States population (p =0.008). In in vitro studies, both AAT and a synthetic inhibitor of serine proteases suppressed M. abscessus infection of monocyte-derived macrophages by up to 65% (p<0.01). AAT may be an anti-RGM host-defense factor, and anomalous AAT phenotypes or AAT deficiency may constitute risk factors for pulmonary disease due to RGM.

Extensively drug-resistant tuberculosis: are we learning from history or repeating it?

Tuberculosis (TB) is an enormous global public health problem. Cases of extensively drug-resistant TB (XDR-TB) are being reported in increasing numbers across the globe. A large outbreak of XDR-TB associated with rapid and nearly universal mortality has been reported among patients with human immunodeficiency virus infection or acquired immunodeficiency disease in South Africa who have been receiving standard TB therapy and antiretrovirals. Epidemiologic features of this outbreak make it highly suspicious for health care-associated transmission. We urge the Infectious Diseases Society of America and its members to increase involvement in ongoing international TB prevention and treatment efforts and to develop a registry of experts in infection control and laboratory and disease management. We urge advocacy for increased funding for domestic and global TB control programs, including expanded access to sputum culture and drug susceptibility testing, as well as funding for TB clinical trials and research capacity. We believe that substandard TB diagnostic tests are not acceptable for TB control in resource-poor countries. We urge the development of shorter, less toxic TB treatment and prevention regimens. Funding of TB control and research should be reassessed to prevent budget cuts at a time when the disease is killing as many as 2 million people a year.

Pharmacokinetic Evaluation of para‐Aminosalicylic Acid Granules

Study Objective. To determine the bioavailability and renal elimination of para‐aminosalicylic acid (PAS) and its inactive metabolite acetyl‐para‐aminosalicylic acid (AcPAS) from a new PAS formulation.

Serodiagnosis of Mycobacterium avium complex pulmonary disease in the USA

Diagnosis of Mycobacterium avium complex pulmonary disease (MAC-PD) can be difficult. A previous study from Japan reported the usefulness of a serodiagnostic test for MAC-PD. The objective of this study was to evaluate the usefulness of the test in similar patients in the USA. 100 patients with known or suspected MAC-PD and 52 healthy volunteers were enrolled into the study at National Jewish Health, Denver, CO, USA. Serum glycopeptidolipid core immunoglobulin A antibody levels were measured with an enzyme immunoassay (EIA) kit and routine clinical evaluations were performed. The patients were divided into two groups based on clinical evaluation: 87 patients with MAC-PD that met American Thoracic Society criteria, and 13 who did not meet the criteria. The sensitivity and specificity (cut-off point 0.3 U·mL−1) of the serodiagnostic test for diagnosing MAC-PD were 70.1% and 93.9%, respectively. Among the 44 patients in the MAC-PD group with two or more positive sputum cultures within the previous 6 months, sensitivity was 81.8%. The EIA kit demonstrated good sensitivity and specificity for the identification of MAC-PD, particularly in patients with two or more positive cultures, and may be useful for rapid MAC-PD diagnosis.

Potential Interaction between Itraconazole and Clarithromycin

Three patients negative for human immunodeficiency virus infection were admitted for pulmonary Mycobacterium avium complex (MAC) and aspergillosis infections. They were treated with different drug combinations, but all regimens included clarithromycin for MAC and itraconazole for aspergillosis. All patients experienced an increase in clarithromycin concentrations and clarithromycin:14‐OH‐clarithromycin ratio compared with expected range values. They had no clinical side effects. The time course suggested a possible interaction between clarithromycin and itraconazole, presumably through itraconazoles effects on cytochrome P450 3A4 activity. A bidirectional interaction cannot be ruled out. The data suggest that, when necessary, these two drugs can be administered together safely. Further investigation is necessary to determine the extent and clinical consequences of coadministration in humans.

Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement

Nontuberculous mycobacterial pulmonary diseases (NTM-PD) are increasingly recognised as opportunistic infections of humans. These chronic pulmonary infections have two main presentations. The first is a fibro-cavitary disease, that occurs in patients with pre-existing pulmonary diseases, such as chronic obstructive pulmonary disease, bronchiectasis, previous tuberculosis or other structural lung disease. The second presentation is a nodular-bronchiectatic disease of primarily the lingula and middle lobe that tends to affect a middle-aged and elderly female population [1]. Improving treatment outcome reporting in NTM disease: NTM-NET (@ntmnet) consensus statement on treatment outcome definitions http://ow.ly/c6IC30iwLM4