Tratamiento antibiótico para la infección pulmonar por micobacterias no tuberculosas en pacientes con fibrosis quística
Resumen
Antecedentes
Las micobacterias no tuberculosas son micobacterias, diferentes de las micobacterias del complejo Mycobacterium tuberculosis y se hallan con frecuencia en el medio ambiente. Las especies de micobacterias no tuberculosas (mayormente el complejo Mycobacterium avium y la Mycobacterium abscessus) están aisladas de las vías respiratorias de aproximadamente un 5% a un 40% de los individuos con fibrosis quística; pueden causar neumopatía en pacientes con fibrosis quística y provocar una aceleración del deterioro de la función pulmonar e incluso la muerte en determinadas circunstancias. Si bien existen guías para el tratamiento antimicrobiano de la enfermedad pulmonar por micobacterias no tuberculosas, dichas recomendaciones no son específicas para los pacientes con fibrosis quística, además no queda claro qué régimen antibiótico podría ser el más eficaz para tratar a estos pacientes. Ésta es una actualización de una revisión anterior.
Objetivos
El objetivo de esta revisión era comparar el tratamiento antibiótico con ningún tratamiento antibiótico, o comparar diferentes combinaciones de tratamiento antibiótico, para las infecciones pulmonares por micobacterias no tuberculosas en pacientes con fibrosis quística. El objetivo principal fue evaluar el efecto del tratamiento en la función pulmonar y las exacerbaciones pulmonares y cuantificar los eventos adversos. Los objetivos secundarios fueron evaluar los efectos del tratamiento en la cantidad de bacterias en el esputo, la calidad de vida, la mortalidad, los parámetros nutricionales, las hospitalizaciones y la administración de antibióticos orales.
Métodos de búsqueda
Se realizaron búsquedas en el registro de ensayos del Grupo Cochrane de Fibrosis Quística (Cochrane Cystic Fibrosis and Genetic Disorders Group), compilado a partir de búsquedas de bases de datos electrónicas y búsquedas manuales de revistas y libros de resúmenes de conferencias. Fecha de la última búsqueda: 2 de septiembre de 2016.
También se realizaron búsquedas en el registro de ensayos en curso y en las listas de referencias de los artículos y revisiones pertinentes. Fecha de la última búsqueda: 3 de noviembre de 2016.
Criterios de selección
Cualquier ensayo controlado aleatorizado que comparara los antibióticos para las micobacterias no tuberculosas con ningún tratamiento antibiótico, y un régimen de antibióticos para las micobacterias no tuberculosas comparado con otro régimen de antibióticos para las micobacterias no tuberculosas, en individuos con fibrosis quística.
Obtención y análisis de los datos
No se recopilaron datos porque en el único ensayo identificado por la búsqueda no se pudieron obtener de la empresa farmacéutica datos específicos sobre las personas con fibrosis quística.
Resultados principales
Se identificó un ensayo completado a través de la búsqueda, pero no se pudieron obtener de la empresa farmacéutica datos específicos sobre las personas con fibrosis quística.
Conclusiones de los autores
Esta revisión no halló evidencia sobre la efectividad de los diferentes tratamientos antimicrobianos para la enfermedad pulmonar con micobacterias no tuberculosas en pacientes con fibrosis quística. Hasta no disponer de dicha evidencia, lo más razonable es que los médicos cumplan las guías de práctica clínica publicadas para el diagnóstico y el tratamiento de la enfermedad pulmonar nodular o bronquiectásica causada por el complejo Mycobacterium avium o Mycobacterium abscessus en pacientes con fibrosis quística.
PICO
Resumen en términos sencillos
Tratamiento antibiótico para las micobacterias no tuberculosas en pacientes con fibrosis quística
Las micobacterias no tuberculosas son bacterias que pertenecen a la misma familia de la tuberculosis y se suelen hallar en el suelo y en el agua. Estas bacterias pueden encontrarse en los pulmones de los pacientes con fibrosis quística y pueden empeorar la función pulmonar. Aunque existen guías sobre qué antibióticos se deben usar para tratar la infección pulmonar causada por estas bacterias, las recomendaciones no son específicas para los pacientes con fibrosis quística. Tampoco queda claro cuáles son los antibióticos más eficaces. El objetivo principal de esta revisión era determinar si el tratamiento con diferentes combinaciones de antibióticos para la infección micobacteriana no tuberculosa podría mejorar la función pulmonar o reducir la frecuencia de las infecciones respiratorias en pacientes con fibrosis quística. Se encontró un ensayo controlado aleatorizado pero incluyó tanto a personas con como sin fibrosis quística y no se pudo obtener información específica sobre los individuos con fibrosis quística, por lo que no se pudo incluir la información en esta revisión. Hasta que dicha información esté disponible, los médicos deben seguir las guías actuales para el diagnóstico y tratamiento de las infecciones pulmonares causadas por las micobacterias no tuberculosas en la población general.
Pregunta de la revisión
Se revisó la evidencia sobre el uso de antibióticos para tratar la infección por micobacterias no tuberculosas en pacientes con fibrosis quística.
Antecedentes
Las micobacterias no tuberculosas son bacterias que pertenecen a la misma familia de la tuberculosis y se suelen hallar en el suelo y en el agua. Estas bacterias pueden encontrarse en los pulmones de los pacientes con fibrosis quística y pueden empeorar la función pulmonar. Aunque existen guías sobre qué antibióticos se deben usar para tratar la infección pulmonar causada por estas bacterias, las recomendaciones no son específicas para los pacientes con fibrosis quística. Tampoco queda claro qué antibióticos funcionan mejor. El objetivo principal de esta revisión fue mostrar si tratar o no la infección micobacteriana no tuberculosa con diferentes combinaciones de antibióticos mejora la función pulmonar o reduce la frecuencia de las infecciones respiratorias en pacientes con fibrosis quística.
Fecha de la búsqueda
La evidencia está actualizada hasta: 2 de septiembre de 2016.
Características de los estudios
Se encontró un ensayo controlado aleatorizado pero incluyó tanto a personas con como sin fibrosis quística y no se pudo obtener información específica sobre los individuos con fibrosis quística, por lo que no se pudo incluir la información en esta revisión.
Resultados clave
Hasta que se disponga de datos de ensayos controlados aleatorizados para personas con fibrosis quística, los médicos deben seguir las guías actuales para el diagnóstico y tratamiento de las infecciones pulmonares causadas por las micobacterias no tuberculosas en la población general.
Authors' conclusions
Background
Description of the condition
Although cystic fibrosis (CF) is the most common life‐shortening genetic disease in the Caucasian population, there has been a dramatic improvement in the median survival age of individuals with CF over the past several decades (CF Foundation 2013; CF Canada 2014; Gibson 2003). As people with CF live longer, they are more likely to become colonized with environmental organisms such as nontuberculous mycobacteria (NTM).
NTM are mycobacteria other than those in the Mycobacterium tuberculosis (M tuberculosis) complex, which includes M tuberculosis (Mandell 2010). They are commonly found in the environment and have been isolated from soil, water, animals, plants and birds (Falkinham 2001). Species of NTM can cause disease, such as lymphadenitis and bronchopulmonary infection, in both immunocompromised as well as immunocompetent people (Mandell 2010).
In the 1990s, NTM species began to be regularly cultured from the respiratory tract of individuals with CF around the world. Original studies by Olivier estimated the prevalence of NTM isolation from individuals with CF to be approximately 13% in the United States of America (Olivier 2003). The majority of NTM species isolated in this study were Mycobacterium avium (M avium) complex followed by Mycobacterium abscessus (M abscessus). Subsequent studies have indicated that the prevalence of NTM isolation in the CF population ranges from 5% to 40% (Esther 2005; Fauroux 1997; Levy 2008; Olivier 2003; Sermet‐Gaudelus 2003; Campos‐Herrero 2016). Depending on the study and patient population, either M abscessus complex or M avium complex are the most common NTM species isolated. The M avium complex consists of M avium and M intracellulare (Mandell 2010) and the M abscessus complex is generally accepted to consist of M abscessus, M bolletii and M massiliense (Blauwendraat 2012; Tortoli 2016). People with CF who have M avium complex tend to be older, have better lung function, have a higher rate of Staphylococcus aureus (S aureus) and a lower rate of Pseudomonas aeruginosa (P aeruginosa) infection, suggesting a healthy survivorship effect in colonized individuals (Olivier 2003; Roux 2009). In contrast, M abscessus infection is more prevalent than M avium complex in children with CF and may lead to more deleterious clinical outcomes (Catherinot 2013; Esther 2005; Pierre‐Audigier 2005; Qvist 2015). Additional factors such as geographical location and microbiological processing methods may also impact the epidemiology of NTM in people with CF. Specific decontamination procedures in the processing of CF sputum have been recommended to improve the recovery of NTM on culture and the optimal decontamination method may be different for sputum from children compared to sputum from adults (Radhakrishnan 2009; Whittier 1993). As NTM are environmental organisms, certain regions such as the mid‐Atlantic and southeastern United States of America are known to have high incidence of mycobacterial disease which has been linked to the high prevalence of NTM in the soil (Brooks 1984; Satyanarayana 2011). Outbreaks of NTM pulmonary disease have also been described in CF populations in tropical regions such as Hawaii (United States) (Johnston 2016).
The presence of NTM species in the respiratory tract of people with CF signifies NTM infection, but NTM pulmonary disease causing clinical deterioration is more difficult to define in a progressive lung disease such as CF. The American Thoracic Society (ATS) in collaboration with the Infectious Diseases Society of America (IDSA) has outlined microbiological, clinical and radiological criteria for NTM disease (Griffith 2007). When examining the effects of NTM infection on the progression of CF lung disease, evidence suggests that CF cases that meet the ATS definition of NTM disease are more likely to show progression of findings on computed tomography of the chest and have a greater decline in lung function, particularly among children (Esther 2005; Griffith 2007; Olivier 2003). In addition, infection with the M abscessus species, in contrast to infection with the M avium complex, leads to an increased rate of decline in lung function in people with CF compared to those uninfected with NTM, even after controlling for potential confounders (Esther 2010). There is also a report of an outbreak of M abscessus complex among individuals with CF in a lung transplant center resulting in 60% mortality (Aitken 2012). Thus, although the distinction between simple infection and disease is often unclear, there are cases of NTM pulmonary disease in people with CF that cause worse clinical outcomes and require antimicrobial treatment.
Description of the intervention
The choice of antibiotics to treat NTM pulmonary infection depends on the species of NTM isolated and is based on data primarily from people who don't have CF. Pulmonary disease caused by M avium complex is usually treated with a combination of a macrolide (clarithromycin or azithromycin), rifampin or rifabutin and ethambutol (Griffith 2007). Of the known rapidly growing pathogenic mycobacteria, M abscessus is the most resistant to antimicrobials and initial treatment is frequently combination therapy with clarithromycin, amikacin and either cefoxitin or imipenem. Curative therapy of M abscessus lung disease is more likely to be achieved with the addition of surgical resection, but this is unlikely to be possible in a diffuse disease such as CF (Griffith 1993). Alternative therapies may be considered if in vitro susceptibility testing demonstrates resistance to these initial agents. However, in vitro susceptibility results do not always predict in vivo clinical response to therapeutic agents as clinical response depends partly on local and host defense systems (Maniu 2001). For M abscessus species, there is no correlation between in vitro susceptibility results to any agent and clinical response to the treatment of pulmonary disease by these agents. Nonetheless, alternative classes of antibiotics can be considered if there is a lack of clinical response, concerns for drug toxicity or in vitro resistance noted with initial antimicrobial agents. Based on multiple studies of in vitro antimicrobial susceptibility testing of M abscessus isolates, alternative antibiotics include: ciprofloxacin (susceptibility range 3% to 82%); gatifloxacin (7% to 91% susceptible); moxifloxacin (8% to 88% susceptible); linezolid (32% susceptible); and tigecycline (100% susceptible) (Gayathri 2010; Miyasaka 2007; Park 2008; Wallace 2002; Yang 2003). It is important to note that M abscessus isolates may be intrinsically resistant to macrolides due to the expression of a novel erm gene (Nash 2009). There is some evidence to suggest that clarithromycin induces greater erm(41) expression and thus higher macrolide resistance than azithromycin in M abscessus infection; both macrolides appear to be equally effective against M massiliense species (Choi 2012; Roux 2015). In addition, people with CF may have been previously treated with antibiotics such as ciprofloxacin or azithromycin (for P aeruginosa) or linezolid (for methicillin‐resistant S aureus (MRSA)) (Waters 2012a) and their NTM species may thus already be resistant in vitro to these agents.
How the intervention might work
There are several case reports of people with CF with NTM infection and severe lung disease clinically responding to antimicrobial therapy which targets the specific NTM species leading to eradication of the organism (Fauroux 1997). Antibiotic treatment of NTM pulmonary infections thus has the potential to improve lung function, reduce the frequency of pulmonary exacerbations and eliminate the bacteria from the lung in people with CF. However, there are no data on the effectiveness of early antibiotic therapy to eradicate NTM or chronic antimicrobial suppressive treatment of NTM to prevent lung function decline in CF patients. Early antibiotic therapy to eradicate NTM consists of initiation of antimicrobial treatment on first isolation of an organism in order to eliminate it from the CF lung. Chronic antimicrobial suppressive treatment refers to prolonged antimicrobial therapy to reduce the bacterial burden of the organism in the lung. Furthermore, it is not clear what is the optimal choice of antibiotics or route of antibiotic administration (oral, intravenous or inhaled) with which to treat these patients.
Why it is important to do this review
This review is important because NTM pulmonary infections affect a significant proportion of people with CF worldwide. Data on the treatment and management of these infections is currently extrapolated from a non‐CF population and its applicability to CF lung disease is unclear. It is thus necessary to determine whether there are antibiotic treatments for NTM lung infections which result in improved clinical or microbiological outcomes in people with CF.
This is an update of a previously published version of the review (Waters 2012b; Waters 2012c; Waters 2014).
Objectives
To compare antibiotic treatment to no antibiotic treatment, or to compare different combinations of antibiotic treatment, for NTM lung infections in people with CF.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials.
Types of participants
Adults and children (ages 0 to 18 years) diagnosed with CF (with all levels of disease severity), confirmed with sweat test or genetic testing, or both, who have NTM pulmonary infection (defined as at least two respiratory specimens positive by culture for NTM ‐ post hoc change) will be included. Individuals with a respiratory tract specimen that is positive on stain for acid‐fast bacilli (AFB) but culture negative for NTM will not be included. Respiratory tract specimens will include sputum, lung biopsy or bronchoalveolar lavage specimens. Individuals with CF who have received a lung transplant will be excluded.
Types of interventions
The intervention was antibiotics to treat NTM pulmonary infections. We planned to compare NTM antibiotics to no antibiotic treatment as well as compare different NTM antibiotic regimens. Antibiotics included single or multiple antibiotics, oral, inhaled or intravenous antibiotics. Surgical interventions were excluded.
Types of outcome measures
Primary outcomes
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Lung function
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forced expiratory volume in one second (FEV1) (absolute values litres or per cent (%) predicted or both)
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forced vital capacity (FVC) (absolute values litres or % predicted or both)
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mid‐expiratory flow (FEF25‐75) (absolute values litres or % predicted or both)
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Pulmonary exacerbations, defined as an increase in respiratory symptoms requiring intravenous antibiotic therapy (Fuchs 1994) (if pulmonary exacerbations are not defined in the study, data from that study relating to pulmonary exacerbations will not be reported in this review)
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number of pulmonary exacerbations
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time between pulmonary exacerbations
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time to subsequent exacerbation
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Adverse events (proportion of participants who had to withdraw or changed therapy)
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mild: transient event, no treatment change, e.g. rash, nausea, diarrhoea
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moderate: treatment discontinued, e.g. nephrotoxicity, ototoxicity, hepatitis, visual impairment
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severe: causing hospitalization or death
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Secondary outcomes
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Quality of life (QoL) (as measured by a validated QoL score, i.e. CFQoL (Gee 2000), CFQ‐R (Quittner 2009))
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Mortality
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Nutritional parameters
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weight
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height
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body mass index (BMI)
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Hospitalizations
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number of hospitalizations
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duration (days)
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Use of oral antibiotics
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Quantitative sputum mycobacterial culture (decrease in quantity or eradication) (post hoc change)
Search methods for identification of studies
Electronic searches
We attempted to identify relevant trials from the Group's Cystic Fibrosis Trials Register using the terms: nontuberculous mycobacteria [NTM] AND antibiotics.
The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), weekly searches of MEDLINE, a search of Embase to 1995 and the prospective handsearching of two journals ‐ Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cystic Fibrosis and Genetic Disorders Group website.
Date of last search of the CF Trials Register: 02 September 2016.
We also checked the National Institutes of Health (NIH) sponsored website www.clinicaltrials.gov for any ongoing trials (search terms: nontuberculous mycobacteria, atypical mycobacteria, cystic fibrosis) and contacted the authors or manufacturers for potential interim results.
Date of last search of www.clinicaltrials.gov : 03 November 2016.
Searching other resources
We planned to check the reference lists of all trials identified for any further relevant trials.
Data collection and analysis
One completed trial was identified by the searches, but data specific to individuals with CF could not be obtained from the pharmaceutical company so we were unable to carry out the planned analysis as detailed below. However, if in future updates of this review we are able to obtain data from any trials, we plan the following analysis.
Selection of studies
The two authors (VW, FR) will independently apply the inclusion criteria to all potential trials. The authors will not be blinded to the trials. If a disagreement occurs, it will be resolved by discussion with a third person (Nikki Jahnke (NJ)).
Data extraction and management
Using a data collection form, two authors (VW, FR) will independently obtain data from published reports or from trial investigators. If a disagreement occurs, the authors will resolve this by discussion with a third person (NJ). In addition to information about trial references and authors and verification of trial eligibility, the data collection form includes information about the methods of the trial (e.g. trial duration, type of trial, blinding, number of dropouts and potential confounders). When possible, the authors will extract data on sequence generation and allocation concealment. The authors will report characteristics of the trial participants including age, sex and setting of the trial on the form. Furthermore, they will also describe the intervention with regards to type of antibiotic, route of delivery, doses and length of treatment. The authors will initially analyze data from trials with different types of antibiotic, routes of delivery, doses and lengths of treatment all together and then separately in subgroup analyses (e.g. data from trials comparing oral antibiotic NTM treatments ‐ see below). The authors will collect data for all randomized participants and attempt to collect the following data: the mean change (before and after antibiotic therapy) in FEV1 and FVC, FEF25‐75; the mean hospital length of stay; the time to subsequent pulmonary exacerbation; the number of adverse events; the mean QoL score after antibiotic therapy; the number of mortalities and change in weight (before and after antibiotic therapy) (see Types of outcome measures for a complete list of outcomes). For each mean value, the authors will also obtain the standard deviation (SD) (variation from the average). For time to subsequent exacerbation, they will try to obtain log‐rank estimates and Cox model estimates.
Given that NTM pulmonary infections are generally treated with more long‐term antibiotics, the authors plan to measure outcomes at the following time points: one month and up to six months; six months and up to one year; and one year or longer interval. They will measure the outcome 'Time to subsequent pulmonary exacerbation' in monthly intervals after these time points. The authors will also consider outcomes measured at other time points.
Assessment of risk of bias in included studies
The authors will assess the included trials for the following types of bias: selection bias (bias in choosing study participants); performance bias (bias in the care of study participants); attrition bias (bias in how participant loss to follow up is handled); detection bias (biased assessment of outcome); and reporting bias (bias in the reporting of study outcomes) (Higgins 2011b) using the following strategies as outlined below.
Assessment of generation of allocation sequences
They will assess each trial as to the generation of allocation sequences:
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low risk of bias: if allocation sequence is suitable to prevent selection bias (i.e. random numbers table, drawing envelopes, tossing a coin, throwing dice etc);
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high risk of bias: if allocation sequence could be related to prognosis and thus introduce selection bias (i.e. assigning participants based on case record number, date of birth, date of admission etc);
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uncertain risk of bias: if the trial is described as randomised but the method used to generate the allocation sequence is not stated.
Assessment of concealment of allocation sequences
They will also assess the method used to conceal the allocation sequences in each trial:
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low risk of bias: if participants and investigators cannot predict which group the participant will be assigned to (i.e. coded drug containers, central randomisation, numbered, sealed, opaque envelopes etc);
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high risk of bias: if participants and investigators can predict which group the participant will be assigned to and thus introduce selection bias (i.e. open allocation schedule, non‐opaque envelopes etc);
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uncertain risk of bias: if the method of concealing the allocation sequence is not described.
Assessment of blinding
In order to determine the potential for performance and detection bias, the authors will assess each trial with respect to the degree of blinding:
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the participant is blinded to participant assignment;
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the care provider is blinded to participant assignment;
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the investigator measuring study outcomes is blinded to participant assignment.
There will be a high risk of bias if there is no blinding with respect to one or more of the above categories. There will be a low risk of bias if the trial is blinded to all three. There will be an uncertain risk of bias if the trial does not specify the degree of blinding in each of the three categories.
Incomplete outcome data
To assess for the possibility of attrition bias, the authors will examine each trial with respect to:
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whether or not it was stated how many participants were lost to follow‐up and why they were lost to follow‐up;
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whether or not an intention‐to‐treat analysis was used (i.e. inclusion in the final analysis of all randomized participants into a trial in the groups to which they were randomized irrespective of what happened subsequently).
There will be a high risk of bias if an intention‐to‐treat analysis was not used. There will be a low risk of bias if the number and reason for loss of follow‐up is specified and if an intention‐to‐treat analysis was used. There will be an uncertain risk of bias if the trial does not specify the above outlined information.
Assessment of selective reporting
The authors will review the included trials for selective reporting (Higgins 2011b). They will compare the original trial protocols with the published paper(s) to ensure all planned outcomes are reported. If the original trial protocols are not available, they will review the 'Methods' and 'Results' sections and use their discretion to determine if selective reporting has occurred.
Assessment of other potential sources of bias
The authors will also review the included trials for other potential sources of bias that will threaten the validity of the trial. These will include: early cessation of the trial; if the interim results affect the trial conduct; deviation from the trial protocol; inappropriate administration of a co‐intervention; contamination; the use of an insensitive instrument to measure outcomes; selective reporting of subgroups; fraud; inappropriate influence of funding agencies and industry sponsorship; null bias due to the interventions being poorly delivered; or the existence of a pre‐randomization of an intervention that could affect the effects of the randomized intervention (Higgins 2011a).
Incorporating assessments of study validity in reviews
The authors plan to weigh trials according to their assessed validity by using the inverse of the variance for the estimated measure of effect. If they consider there was a high risk of bias, they will investigate the effects of this with a sensitivity analysis (see below).
Measures of treatment effect
For dichotomous data, the authors will gather information on participants randomized to each treatment group (antibiotics versus no antibiotics or one antibiotic regimen versus another regimen), based on an intention‐to‐treat analysis, and the number of events. They plan to include interim results from individual randomized participants with CF from ongoing studies in the analysis. They will define time points for each trial outcome according to when it was measured (one to six months, six months up to one year, one year or over). They will analyze trial outcomes separately according to these time points. The authors plan to pool the treatment effect across studies to determine a relative risk (RR) and its 95% confidence intervals (CIs) for each outcome.
For continuous data, the authors will calculate the difference between the mean (average) values (MD) of treatment effect for each group, the number in each group and the standard deviation (SD). As a summary statistic across trials, they will use the MD if the same scale is used, or the standardised mean difference (SMD) if different scales are used (e.g. QoL measurements) both with 95% CIs. For time‐to‐event data, most trials use Kaplan‐Meier survival analysis. The authors will thus collect log‐rank estimates and Cox model estimates to subsequently summarize the time‐to‐event data as a hazard ratio (HR) with 95% CIs (Deeks 2011; Parmar 1998).
Unit of analysis issues
The authors will include data from cluster‐randomized trials if the information is available. For clusterrandomized trials, they will calculate the intra‐cluster correlation coefficient (ICC) according to Donner (Donner 2001). They will also include data from cross‐over trials if the information is available. Continuous data from cross‐over trials will be analyzed using one of three approaches: treat the study as a parallel trial and pool the interventional periods and compare these to the pooled placebo periods; include data from the first period only and approximate a paired analysis; impute missing SDs (Higgins 2011c). Cross‐over trials with dichotomous outcomes require more complicated analysis methods and for this the authors will consult with a statistician (Elbourne 2002).
Dealing with missing data
Data are often missing for participants who are lost to follow‐up. In these situations, the authors will perform an available‐case analysis (analyzing data for every participant for whom the outcome is obtained). They will report the percentages of participants from whom no outcome data were obtained on the data collection form. They will include data on only those whose results are known, using as a denominator the total number of people who completed the trial for the particular outcome in question. The authors will consider variation in the degree of missing data across trials as a potential source of heterogeneity.
Assessment of heterogeneity
In performing a meta‐analysis, the authors will measure the variability of results between trials (heterogeneity) using the I2 method (with CIs) outlined by Higgins (Higgins 2003). The I2 statistic describes the percentage of total variation across trials that is due to heterogeneity rather than chance. It is calculated using Cochran's heterogeneity statistic and the degrees of freedom. The I2 statistic can range from 0% to 100%. A value of 0% indicates no observed heterogeneity and larger values show increasing heterogeneity. The authors will consider a value greater than 50% as substantial heterogeneity. They will also visually inspect the forest plot to assess the heterogeneity between trials.
Assessment of reporting biases
To investigate whether the review is subject to publication bias, and if they are able to include sufficient trials (at least 10), the authors will construct a funnel plot. In the absence of bias, the plot should resemble a symmetrical inverted funnel (Sterne 2011). If there is asymmetry, the authors will consider publication bias and other reasons (such as location biases, true heterogeneity, poor methodological quality of smaller trials etc) as a potential cause.
Data synthesis
If the authors consider that the trials are clinically similar enough to combine (e.g. studies comparing different antibiotic combinations to treat pulmonary exacerbations in participants with NTM infection), they will investigate statistical heterogeneity as outlined below. If there is no substantial heterogeneity, they will calculate the pooled effect estimates using a fixed‐effect model. If they identify substantial heterogeneity (I2 statistic is greater than 50%), they will perform a random‐effects meta‐analysis to incorporate heterogeneity between trials.
Subgroup analysis and investigation of heterogeneity
If the authors find substantial heterogeneity (I2 statistic is greater than 50%) (Higgins 2003), they will explore the potential causes of this (i.e. different types of antimicrobial treatment such as oral, inhaled or intravenous; different participant populations; different species of NTM etc) and if possible (if at least five trials are included for that outcome) conduct subgroup analyses of the trials. For example, trial results may vary if different types of antibiotic treatment are used (e.g. oral, inhaled or intravenous) for the treatment of pulmonary infection, or different treatment durations (e.g. six months versus one year). There may also be differences depending on whether antibiotics are used to treat a first‐time infection (eradication) versus an established, chronic infection (when more than 50% of cultures are positive in the previous 12 months). Finally, there may be differing effects of antibiotic treatment of NTM pulmonary infection depending on the type of NTM species isolated (e.g. antimicrobial treatment of M abscessus pulmonary infections may show more of a clinical benefit than treatment of M avium complex infections).
Sensitivity analysis
If the authors are able to include at least 10 trials in the review, they will perform a sensitivity analysis to determine whether the conclusions are robust to decisions made during the review process such as inclusion or exclusion of particular studies from a meta‐analysis, imputing missing data or choice of a method for analysis. They will investigate whether changing which studies are included, based on their assessment of the risk of bias (initially including all trials and then excluding any with a high risk of bias) or changing our chosen statistical model (i.e. random‐effects model compared to a fixed‐effect model) changes the results of the review. If the sensitivity analyses do not significantly change the results presented in the review, it strengthens the confidence that can be placed in these results. The authors will present the results in an influence plot, as appropriate.
Results
Description of studies
We have identified one randomized controlled trial which has been completed but it included both individuals with and without CF (Olivier 2016). We have contacted the trial investigators and the pharmaceutical company who sponsored the trial (Insmed), but to date they have declined to provide any data specific to individuals with CF. For this reason, we currently list this trial as 'Awaiting classification' and we will assess it for inclusion if the data specific to individuals with CF becomes available.
This phase 2, randomized, double‐blind controlled trial included adults (both with and without CF) who met criteria for pulmonary non‐tuberculous mycobacterial disease defined by the ATS and the IDSA. Participants had received ongoing multi‐drug treatment (based on ATS and IDSA guidelines) for at least six months prior to screening and had persistently positive cultures for M avium complex or M abscessus. Participants were randomized 1:1 to either liposomal amikacin for inhalation at a dose of 590 mg or placebo (empty liposomes) once daily via the PARI Investigational eFlow® Nebulizer; this regimen was added to their ongoing stable multi‐drug regimen for 84 days. At the end of this period, participants could consent to receive open‐label treatment with daily liposomal amikacin inhaled and their background regimen for an additional 84 days. The primary endpoint was the change from baseline to day 84 on a semi‐quantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6‐minute walk distance and adverse events. The modified intent‐to‐treat population included 89 participants (liposomal amikacin for inhalation n = 44; placebo n = 45); 19% of participants had CF, 64% had predominantly M avium complex infection and 36% had predominantly M abscessus infection.
Risk of bias in included studies
No trials have yet been included in this review.
Effects of interventions
No trials have yet been included in this review.
Discussion
Summary of main results
There were no data from randomized controlled trials of treatment of nontuberculous mycobacteria (NTM) pulmonary infection in people with cystic fibrosis (CF) which could be included in this review. One trial has been listed as 'Awaiting assessment' until we are able to obtain CF‐specific data from the trial sponsor (Insmed) (Olivier 2016).
This trial of liposomal amikacin for inhalation in adults (19% of whom had CF) who met defined criteria for pulmonary NTM disease, had received ongoing multi‐drug treatment for at least six months and had persistently positive cultures for Mycobacterium avium (M avium) complex or Mycobacterium abscessus (M abscessus) (Olivier 2016). In addition to their ongoing multi‐drug regimen, participants were randomized to inhaled liposomal amikacin or placebo for 84 days. Although the primary endpoint of a reduction in semi‐quantitative mycobacterial growth was not achieved, a greater proportion of participants in the liposomal amikacin group (32%) demonstrated sputum conversion (at least one negative mycobacterial sputum culture) than in the placebo group (9%) (P = 0.006); however, most of those in whom sputum conversion was observed did not have CF and were infected with M avium complex rather than M abscessus infection. Those in the liposomal amikacin group also had a greater improvement in the 6‐minute walk test at day 84 (P = 0.017).
Overall completeness and applicability of evidence
The only identified randomized controlled trial to date was in adults only (Olivier 2016). To date, we do not have access to the data for those participants with CF, it is therefore not possible to determine the relevance of these findings to the CF population.
Agreements and disagreements with other studies or reviews
Traditionally, antimicrobial therapy of NTM lung infection (including in people with CF) has been guided by protocols summarized in the statement endorsed by the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) (Griffith 2007).
Most data are available for M avium complex and these recommendations are based on evidence with a highest grade of II (evidence from at least one well‐designed clinical trial without randomization). The initial controlled‐treatment studies were undertaken using only first‐line anti‐tuberculosis (TB) drugs, which have 10 to 100 times less in vitro activity against M avium complex than against Mycobacterium tuberculosis (M tuberculosis). The Research Committee of the British Thoracic Society conducted the first randomized controlled trial of 75 participants with M avium complex pulmonary disease. Participants were randomized to two years of either rifampicin and ethambutol or to rifampicin, ethambutol and isoniazid (British Thoracic Society 2001; British Thoracic Society 2002). Although two thirds of enrolled participants had co‐existing lung disease, it was not specified if any of them had CF. In this trial, there were fewer treatment failures or relapses with the rifampicin, ethambutol and isoniazid regimen compared to the rifampicin and ethambutol regimen (16% versus 41% respectively, P = 0.033). However, there was a suggestion that the rifampicin, ethambutol and isoniazid regimen was associated with higher death rates overall. The advent of the newer macrolides, clarithromycin and azithromycin, was a significant advancement in the treatment of pulmonary disease due to M avium complex, as these drugs have good in vitro and clinical activity against M avium complex (Griffith 2007). Clinical studies of macrolide use with traditional anti‐TB drugs have shown superior sputum conversion rates compared to historical controls (Griffith 1996; Wallace 1994; Wallace 1996). However, in a recent two‐year trial of mycobacterial lung disease, clarithromycin was compared to ciprofloxacin as alternative third drugs to be added to rifampicin and ethambutol and did not demonstrate any superiority in terms of clinical outcomes in people infected with M avium complex (Jenkins 2008).
The other NTM species commonly isolated from the respiratory tract of people with CF is M abscessus. In contrast to M avium complex, M abscessus is uniformly resistant to the standard anti‐tuberculous agents (Griffith 2007). There are few comparative trials of differing antimicrobial interventions for the treatment of pulmonary NTM disease due to M abscessus. Our search identified only one randomized, placebo‐controlled trial testing liposomal amikacin for inhalation (Olivier 2016). Liposomal amikacin is an aminoglycoside drug that has been enveloped in a spherical phospholipid bilayer known as a liposome. This formulation of the drug can be delivered via inhalation to the lower airways where the lipid bilayer fuses with the bacterial cell membrane, allowing delivery of the drug into the cell (Beaulac 1997; Sachetelli 2000). The trial did not achieve its primary endpoint (reduction in semi‐quantitative mycobacterial growth), but showed sputum conversion (at least one negative mycobacterial sputum culture) (P=0.006) and improvement in 6‐minute walk test (P=0.017) at day 84 in the liposomal amikacin group compared to the placebo group. Unfortunately most participants in whom sputum conversion was observed did not have CF and were infected with M avium complex rather than M abscessus infection.
