Phenotypic amikacin resistance may not indicate poor response to amikacin in Mycobacterium avium complex pulmonary disease.

When using amikacin to treat Mycobacterium avium complex pulmonary disease (MAC-PD), a minimum inhibitory concentration resistance breakpoint of ≥64 mcg/mL is recommended. We explored whether amikacin resistance characterized by phenotypic drug susceptibility testing was associated with clinical outcomes or mutational resistance in a retrospective cohort of patients with MAC-PD. Despite little aminoglycoside exposure, amikacin resistance was common in our MAC-PD patients but was not associated with worse outcomes or rrs gene mutations.

The epidemiologic relationship between tuberculosis and non-tuberculous mycobacterial disease: a systematic review.

SETTING: Tuberculosis (TB) rates are decreasing in many areas, while non-tuberculous mycobacteria (NTM) infection rates are increasing. The relationship between the epidemiology of TB and NTM infections is not well understood. OBJECTIVE: To understand the epidemiologic relationship between TB and NTM disease worldwide. DESIGN: A systematic review of Medline (1946-2014) was conducted to identify studies that reported temporal trends in NTM disease incidence. TB rates for each geographic area included were then retrieved. Linear regression models were fitted to calculate slopes describing changes over time. RESULTS: There were 22 studies reporting trends in rates of NTM disease, representing 16 geographic areas over four continents: 75% of areas had climbing incidence rates, while 12.5% had stable rates and 12.5% had declining rates. Most studies (81%) showed declining TB incidence rates. The proportion of incident mycobacterial disease caused by NTM was shown to be rising in almost every geographic area (94%). CONCLUSION: We found an increase in the proportion of mycobacterial disease caused by NTM in many parts of the world due to a simultaneous reduction in TB and increase in NTM disease. Research into the interaction between mycobacterial infections may help explain this inverse relationship.

Isolation of non-tuberculous mycobacteria among patients with pulmonary tuberculosis in Ontario, Canada.

SETTING AND OBJECTIVE: There are limited data regarding the frequency and significance of co-isolating pulmonary non-tuberculous mycobacteria (NTM) in patients with pulmonary tuberculosis (PTB). DESIGN: We identified all patients with culture-proven PTB in Ontario, Canada, in 2004, identified those with NTM 'co-isolation' (≤6 months following initial TB isolate) and determined subsequent NTM isolation over 5 years. RESULTS: In 2004, 369 people in Ontario had culture-proven PTB (average age 46 years, SD 21, 41% female). NTM co-isolation occurred in 11% (40/369), including Mycobacterium avium complex 22/40 (55%), M. xenopi 7/40 (18%), M. gordonae 6/40 (15%) and others 5/40 (13%). Patients with NTM co-isolation were older (55 vs. 45 years, P = 0.004), but had similar sex ratios (females 43% vs. 40%, P = 0.87). Among patients with co-isolation, 23% (9/40) went on to have ≥2 NTM cultures (excluding initial culture), compared with 3% (10/329) in the PTB group (including initial culture, P = 0.0001). In the co-isolation group, the median (quartiles) number of samples collected for mycobacterial study was 6 (4-8) compared to 2 (1-4) in the PTB group (P < 0.0001). CONCLUSIONS: The high frequency of subsequent NTM isolation among patients with NTM co-isolation during PTB may warrant follow-up for potential NTM disease.

The cost of medical management of pulmonary nontuberculous mycobacterial disease in Ontario, Canada.

Treatment of pulmonary nontuberculous mycobacterial (NTM) infection is complex, requiring multiple antibiotics and a prolonged treatment course. We determined the monthly cost of treating patients with pulmonary NTM infections in our clinic, a tertiary care centre in Toronto, Ontario, Canada. We reviewed records of a single clinic at the University Health Network (Toronto) for all patients with pulmonary NTM isolates. Pharmacological and nonpharmacological treatment costs were calculated using a number of Canadian references. 172 patients were reviewed, 91 of whom were treated pharmacologically. The median total duration and cost per treated patient were 14 months (interquartile range (IQR) 9-23 months) and CAD 4,916 (IQR CAD 2,934-9,063), respectively. Median monthly drug treatment cost was CAD 321 (IQR CAD 254-458) for all patients, CAD 289 (IQR CAD 237-341) for patients receiving exclusively oral antibiotics and CAD 1,161 (IQR CAD 795-1,646) for patients whose treatment included i.v. antibiotics. The most costly oral regiment consisted of a fluroquinolone, macrolide and rifampin. In multivariable analysis, Mycobacterium abscessus infection, i.v. therapy and Mycobacterium xenopi infection were all associated with increased monthly treatment costs. The direct medical costs of NTM infections are substantial. Less expensive alternative therapies might be most helpful for M. abscessus infection and when i.v. antibiotics are deemed necessary.

A 21-year-old man with systemic-onset juvenile rheumatoid arthritis, cough and progressive dyspnea.

Primary or nonobstructive, endogenous lipoid pneumonia is a rare clinical entity usually associated with an underlying systemic disease. The present report describes a case involving a 21-year-old man with systemic-onset juvenile rheumatoid arthritis who developed primary endogenous lipoid pneumonia. Multiple treatment regimens were attempted; however, definitive management was only achieved through double-lung transplantation.

Pulmonary Mycobacterium xenopi infection in non-HIV-infected patients: a systematic review.

SETTING: The incidence of Mycobacterium xenopi infections is increasing worldwide. The characteristics and optimal management of patients with pulmonary M. xenopi infections have not been well established. METHODS: Systematic review of English- and French-language studies reporting at least two cases of microbiologically confirmed M. xenopi lung infection. Studies were independently reviewed by two reviewers. We described the risk factors and clinical presentation of advanced infection, and examined the impact on clinical success and mortality of including individual antimycobacterial drugs in the treatment regimen. RESULTS: A total of 48 studies reporting on 1255 subjects were included. The majority were retrospective case series. There was marked heterogeneity among the studies. Patients were generally middle-aged men with a history of obstructive lung disease or prior tuberculosis, presenting with an upper lobe cavitary infection. There was no clear association between administration of particular drugs and clinical success or mortality. CONCLUSION: We could not demonstrate any advantage of specific drugs in the treatment of pulmonary M.xenopi infection. Observations from the pooled data are likely subject to significant confounding and selection biases. The inability to make firm conclusions on the optimal management of this increasingly common infection strongly underscores the need for further research.

Macrolides in the treatment of bronchiolitis obliterans in allograft recipients.

Bronchiolitis obliterans (BO) is a serious complication of hematopoietic SCT (HSCT). The condition is believed to be the result of an inflammatory part of the GVHD. Although many BO patients receive immunosuppressive therapy, there is no clear evidence that therapeutic interventions have a positive impact. In the last 20 years, it has been recognized that macrolides have immunomodulatory effects beyond their antibiotic effect. Recent data suggest also that the use of macrolides in BO post HSCT may halt disease progression. Our objectives are to give the readers information on the background of BO post HSCT, to review the immunomodulatory properties of macrolides in general and specifically in pulmonary diseases, and to summarize the current knowledge of macrolide benefits in BO therapy. Research into macrolide immunomodulation for chronic pulmonary disorders, such as diffuse panbronchiolitis and cystic fibrosis, shows consistent positive effects. The use of macrolides for other types of pulmonary inflammatory complications is yet to be proved. The benefit for BO post HSCT was shown only in a small non-randomized trial. Additional in vivo research is needed before developing any firm conclusions.

Antibacterial class is not obviously important in outpatient pneumonia: a meta-analysis.

The aim of the present study was to systematically compare outcomes between antibiotic classes in treating outpatient community-acquired pneumonia, with regard to antibacterials active against atypical organisms, as well as between various antibacterial classes with similar atypical coverage. A meta-analysis was performed on randomised controlled trials of antibacterials for community-acquired pneumonia in outpatients aged > or = 18 yrs. The studies were independently reviewed by two reviewers. Clinical success and mortality were compared between different oral antibiotic classes, and antibacterials with atypical coverage (macrolides and fluoroquinolones) were specifically compared with other antibacterials. In total, 13 eligible studies involving a total of 4,314 patients were included. The quality of the studies was variable. Five studied macrolides and fluoroquinolones, three macrolides and beta-lactams, three fluoroquinolones and beta-lactams and two cephalosporins versus beta-lactams/beta-lactamase inhibitors. No significant difference was detected regarding clinical success or mortality, regardless of atypical coverage or between antibacterial classes with similar atypical coverage. It was not possible to demonstrate any advantage of specific antibacterials for mild community-acquired pneumonia in relatively healthy outpatients. The need for coverage of atypical pathogens in this setting was not apparent. In mild-to-moderate cases of outpatient-treated community-acquired pneumonia, it might be most appropriate to select antibacterials according to side-effects, patient preferences, availability and cost.

Long-term pulmonary function abnormalities and survival after allogeneic marrow transplantation.

We studied long-term pulmonary function testing (PFT) in a retrospective cohort of 6-month survivors of allogeneic marrow transplant (BMT) between 1980 and 1997. Of 593 patients, 73, 71 and 65% had adequate data to assess for obstruction, restriction and diffusion impairments respectively. Over 5 years, mean declines in 1-s forced expiratory volume/forced vital capacity (FEV1/FVC), total lung capacity (TLC) and diffusion were 4, 7 and 17%, respectively. TLC and diffusion tended to subsequently increase. In all, 6, 12 and 35% of patients met criteria for obstruction, restriction and impaired diffusion, respectively. Obstruction was less common in recent transplants (5 vs 15%, P=0.004), while restriction and diffusion impairment rates remained stable. There was significantly greater mortality with obstruction (HR 2.0 (1.04-3.95)), and a nonstatistically significant higher mortality rate with restriction (HR 1.6 (0.95-2.75)), but not with impaired diffusion (HR=0.99 (0.65-1.50)). cGVHD (OR 16.7 (2.2-129.8)) and busulfan (OR 2.9 (1.01-8.24)) were associated with obstruction. Marrow from nonsibling or mismatched donors (OR 4.9 (2.2-10.7)) was associated with restriction. In summary, after BMT, decreased diffusion capacity is common and benign; obstruction has decreased in frequency, is rare without cGVHD, and is associated with mortality; nonsibling and mismatched donor are risk factors for restriction.

Pulmonary function abnormalities after allogeneic marrow transplantation: a systematic review and assessment of an existing predictive instrument.

Pulmonary function testing (PFT) is used to characterize non-infectious pulmonary complications after allogeneic BMT. Identifying high-risk patients could facilitate preventive or early therapeutic measures. The objectives of the study were first, to review available data on PFT changes after BMT and second, to validate a previously published predictive index for PFT obstruction in patients transplanted at one center. For the systematic review, frequency, severity and time course of PFT changes after BMT and for the validation study, retrospective cohort comparing predicted with observed PFT, and calculation of indices of predictive accuracy were summarized. The validation study involved 434 patients from Princess Margaret Hospital, Toronto, Canada, who received their first BMT between 1980 and 1997, survived for at least 6 months and had adequate PFT follow-up. The systematic review included 20 studies. After BMT, decreased diffusion and total lung capacity were common and partially reversible. Obstruction was less common. The validation study of a previously published index, performed in 434 patients, found a sensitivity and specificity of 48% and 68% for identifying patients who develop obstruction. We concluded that PFT changes after BMT are common. A published predictive index is not sufficiently accurate to identify high-risk patients for potential preventive or early therapeutic strategies.

Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia after allogeneic marrow transplantation.

Pneumocystis carinii pneumonia (PCP) poses a serious risk to allogeneic bone marrow transplant (BMT) patients, who are often intolerant of trimethoprim-sulfamethoxazole (TMP-SMX), the traditional first-line prophylactic agents. There are limited published data supporting the use of aerosolized pentamidine (AP) prophylaxis in the BMT population. We assessed the effectiveness of AP in BMT recipients by reviewing the experience at our center. We divided our review into four time periods from January 1990 to March 2000, during which approximately 700 BMTs were performed. The first period includes patients receiving AP treatments from January 1990 to July 1997 (baseline), the second from August 1997 to July 1998 (pre-outbreak), the third from August 1998 to October 1999 (outbreak), and the fourth from November 1999 to March 2000 (post-outbreak). At our center, TMP-SMX is the first-line agent for PCP prophylaxis, which is routinely continued for at least one year, or for the duration of enhanced immunosuppression. During the baseline period, 505 BMTs were performed and 192 patients (38%) received AP for part of their time at risk. Six patients (3%) experienced toxicities requiring discontinuation of AP. Three cases of PCP were diagnosed over 1114 patient-months of treatment in the baseline period. During the last 42 months of the baseline period, 2/154 patients receiving AP and 2 of an estimated 293 patients receiving exclusively oral prophylaxis developed breakthrough PCP (p = 0.61). During the outbreak period, 9 of 180 patients receiving AP developed PCP compared to none in the group receiving exclusively oral prophylaxis. Either changes in our AP protocol during the pre-outbreak period or pentamidine resistance may have led to this failure of prophylaxis. There were no further cases during the 5-month post-outbreak period. Our observed overall breakthrough rate was 12 cases out of 439 patients (2.7%). Our study shows that AP is an effective and well-tolerated second-line agent in preventing PCP post BMT and we recommend its continued use in this regard. However, it should be administered using a well-studied protocol, and only when TMP-SMX is not tolerated.

Applying a prediction rule to identify low-risk patients with community-acquired pneumonia.

STUDY OBJECTIVES: To study the validity of a recently developed community-acquired pneumonia (CAP) severity prediction rule in estimating mortality, to determine its utility in decision making regarding hospitalization, and to assess factors influencing this decision. DESIGN: Retrospective chart review. SETTING: Two sites of the University Health Network, the Toronto General and Toronto Western Hospitals, tertiary-care teaching institutions with a sizable primary-care and secondary-care source of referrals, and a total of 900 beds. PATIENTS: Consecutive patients with CAP admitted between February and June 1996. MEASUREMENTS AND RESULTS: A single trained medical records extractor assembled data to compare our population to that used in developing the CAP prediction rule, in terms of mortality and to assess reasons for hospitalization. Two hundred fifty-five eligible patients were admitted, and 244 charts (96%) were available. Our patients tended to be older, with nearly four times as many residents of chronic care institutions (39% compared with 10%), and had a higher risk class distribution than the published cohort. Risk class-specific mortality was similar in four of five classes. Of the 71 patients in the low-risk classes, 67 had additional reasons for admission; 18 of which were psychosocial (homelessness, substance abuse, or inadequate home supports). CONCLUSIONS: The CAP severity prediction rule estimates mortality well. Admission of low-risk patients was linked to psychosocial and other medical reasons not captured by this rule. The rule can be very useful in assessing the need for hospitalization; however, there remains a significant percentage of patients with a low severity score who may require hospitalization for psychosocial and economic considerations.

Use of guidelines in treating community-acquired pneumonia.

STUDY OBJECTIVES: Guidelines for empiric treatment of community-acquired pneumonia (CAP) have been developed to assist in prescribing appropriate antimicrobials. We studied utilization of guidelines developed by the American Thoracic, Canadian Infectious Diseases, and Canadian Thoracic Societies (ATS, CIDS, and CTS, respectively), physicians' familiarity with them, reasons that prompt deviation from them, and their effects on clinical outcomes. DESIGN: Two-part observational study, with prospective and retrospective groups. SETTING: A 1,100-bed, two-campus, tertiary-care teaching hospital. PATIENTS AND PARTICIPANTS: Patients admitted to the general medical ward who were being treated empirically for CAP and housestaff who provided their care. INTERVENTIONS: Medical residents reported on patients admitted to the hospital with CAP. The charts of all unreported patients admitted with CAP over the same period were reviewed. MEASUREMENTS AND RESULTS: One hundred twenty-two patients were prospectively described and another 130 patients were identified retrospectively. There was no difference in guidelines adherence between the prospective and retrospective groups (81% compared with 80%; p=0.94). Deviation occurred most commonly in suspected aspiration. When physicians believed that they were following guidelines, this was true in 88%. When physicians believed that they were deviating, they were actually adhering in 46%. Guidelines adherence did not alter in-hospital mortality (12% compared with 14%, p=0.92) or length of hospitalization (median, 6 days for both groups). CONCLUSIONS: ATS/CIDS/CTS guidelines for empiric treatment of CAP are widely used in our institution. Future amendments should address aspiration more explicitly. Residents' familiarity with them could be improved. Beneficial effects on outcomes remain unproven.