Dosis diaria única versus dosis diarias múltiples de aminoglucósidos intravenosos para la fibrosis quística
Resumen
Antecedentes
Los pacientes con fibrosis quística, que están crónicamente colonizados por el microorganismo Pseudomonas aeruginosa, suelen requerir ciclos múltiples de antibióticos aminoglucósidos por vía intravenosa para el tratamiento de las exacerbaciones pulmonares. Las propiedades de los aminoglucósidos sugieren que podrían administrarse en concentraciones más altas con menor frecuencia. Ésta es una actualización de una revisión publicada anteriormente.
Objetivos
Evaluar la efectividad y seguridad de una dosis diaria versus dosis múltiples de antibióticos aminoglucósidos por vía intravenosa para el manejo de las exacerbaciones pulmonares en la fibrosis quística.
Métodos de búsqueda
Se realizaron búsquedas en el Registro Especializado de Fibrosis Quística que posee la base editorial del Grupo Cochrane de Fibrosis Quística y Trastornos Genéticos (Cochrane Cystic Fibrosis and Genetic Disorders Group), el cual incluye referencias identificadas a partir de búsquedas exhaustivas en bases de datos electrónicas, búsquedas manuales en revistas relevantes y en libros de resúmenes de congresos.
Fecha de la búsqueda más reciente: 31 de enero 2019.
También se realizaron búsquedas en los registros de ensayos en línea. Fecha de la última búsqueda: 25 de febrero 2019.
Criterios de selección
Todos los ensayos controlados aleatorios, publicados o no publicados, en que se comparó una dosis diaria de aminoglucósidos con dosis diarias múltiples en relación con la eficacia y toxicidad, o ambas, en pacientes con fibrosis quística.
Obtención y análisis de los datos
Los dos autores seleccionaron de forma independiente los estudios para ser incluidos en la revisión y evaluaron el riesgo de sesgo de cada estudio. Los autores también evaluaron la calidad de la evidencia con el uso de los criterios GRADE. Los datos fueron extraídos de forma independiente por cada autor. Se estableció contacto con los autores de los estudios incluidos para obtener información adicional. Por el momento, se obtuvieron los datos no publicados de uno de los estudios incluidos.
Resultados principales
Se identificaron 15 estudios para la inclusión en la revisión. En esta revisión, se incluyeron cinco estudios que informaron sobre los resultados de un total de 354 participantes (de entre 5 y 50 años de edad). Todos los estudios compararon una dosis diaria con tres dosis diarias. Un ensayo cruzado (cross‐over) tuvo 26 participantes que recibieron el tratamiento del primer brazo, pero solo 15 recibieron el segundo brazo. Un estudio presentó un riesgo de sesgo bajo en todos los criterios evaluados; los tres estudios restantes presentaron un riesgo de sesgo de cegamiento alto, pero para otros criterios se consideraron como de riesgo de sesgo incierto o bajo.
Hubo poca o ninguna diferencia entre los grupos de tratamiento en: volumen espiratorio forzado en un segundo, diferencia de medias (DM) 0,33 (intervalo de confianza [IC] del 95%: ‐2,81 a 3,48; evidencia de calidad moderada); capacidad vital forzada, DM 0,29 (IC del 95%: ‐6,58 a 7,16; evidencia de calidad baja); porcentaje de peso para la estatura, DM ‐0,82 (IC del 95%: ‐3,77 a 2,13; evidencia de calidad baja); índice de masa corporal, DM 0,00 (IC del 95%: ‐0,42 a 0,42; evidencia de calidad baja) o en la incidencia de ototoxicidad, riesgo relativo 0,56 (IC del 95%: 0,04 a 7,96; evidencia de calidad moderada). El tratamiento una vez al día en niños probablemente mejoró el cambio porcentual en la creatinina, DM ‐8,20 (IC del 95%: ‐15,32 a ‐1,08; evidencia de calidad moderada), pero no mostró diferencias en los adultos, DM 3,25 (IC del 95%: ‐1,82 a 8,33; evidencia de calidad moderada). Los ensayos incluidos no informaron de patrones de resistencia a los antibióticos ni la calidad de vida.
Conclusiones de los autores
La administración de una dosis y de tres dosis diarias de antibióticos aminoglucósidos parece ser igualmente efectiva para el tratamiento de las exacerbaciones pulmonares de la fibrosis quística. Hay pruebas de una menor nefrotoxicidad en los niños.
PICOs
Resumen en términos sencillos
Administración de antibióticos aminoglucósidos por vía intravenosa una vez al día comparada con la administración varias veces por día en los pacientes con fibrosis quística
Pregunta de la revisión
Se buscó evidencia para mostrar las diferencias entre la administración de antibióticos intravenosos una vez al día en comparación con la administración de antibióticos varias veces al día cuando se tratan los brotes de la enfermedad (exacerbaciones pulmonares) en pacientes con fibrosis quística. Esta revisión es una actualización de una revisión anterior.
Antecedentes
La mayoría de los pacientes con fibrosis quística contraen infecciones pulmonares persistentes y pueden recibir ciclos frecuentes de antibióticos intravenosos para el tratamiento de las exacerbaciones pulmonares. La administración diaria de antibióticos una vez al día reduce el coste y el tiempo implicado, en comparación con varias dosis al día.
Fecha de la búsqueda
La evidencia está actualizada hasta el 31 enero 2019.
Características de los estudios
Esta revisión incluye cinco estudios con un total de 354 niños y adultos. Todos los ensayos compararon una dosis diaria con tres dosis diarias.
Resultados clave
La revisión encontró que al tratar a los pacientes con fibrosis quística para las exacerbaciones pulmonares, la administración de antibióticos una vez al día fue tan efectiva como la administración de antibióticos con mayor frecuencia en cuanto a la función pulmonar y el índice de masa corporal. La revisión también halló que la administración de antibióticos una vez al día pareció ser menos tóxica para el riñón en los niños. No hubo diferencias entre los diferentes esquemas de tratamiento para otros resultados que midieron los estudios.
Aunque la administración una vez al día puede tener la misma eficacia y ser más conveniente que la administración tres veces al día, se recomiendan más estudios para investigar la seguridad a largo plazo de este esquema terapéutico.
Calidad de la evidencia
Se consideró que solo uno de los cinco estudios presentó un riesgo bajo de que cualquier factor de diseño pudiera afectar los resultados. En los cuatro estudios restantes, se pensó que el hecho de que fuera obvio si los antibióticos se administraban una o tres veces al día podía afectar algunas medidas de resultado (p.ej. la función pulmonar). Otros factores de riesgo no fueron claros o presentaron un riesgo de sesgo bajo. Se evaluaron las pruebas de función pulmonar, el índice de masa corporal y la evidencia de que los efectos secundarios (p.ej. toxicidad) fue de calidad moderada a baja.
Authors' conclusions
Summary of findings
| Once‐daily compared with multiple‐daily dosing with intravenous aminoglycosides for cystic fibrosis | ||||||
| Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: once‐daily dosing of intravenous aminoglycosides Comparison: multiple‐daily dosing of intravenous aminoglycosides | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Multiple‐daily dosing of intravenous aminoglycosides1 | Once‐daily dosing of intravenous aminoglycosides | |||||
| Lung function Mean percentage change in FEV1 Follow up: 12 ‐ 14 days | The mean percentage change in FEV1 (% predicted) ranged between 9.66 and 14.9 in the multiple‐daily dosing groups. | The mean percentage change in FEV1 (% predicted) was 0.33 higher (2.81 lower to 3.48 higher) in the once‐daily dosing groups. | NA | 289 | ⊕⊕⊕⊝ | |
| Lung function Mean percentage change in FVC (% predicted) Follow up: 12 ‐ 14 days | The mean percentage change in FVC (% predicted) ranged between 12.2 and 13.8 in the multiple‐daily dosing groups. | The mean percentage change in FVC (% predicted) was 0.29 higher (6.58 lower to 7.16 higher) in the once‐daily dosing groups. | NA | 70 (2 studies) | ⊕⊕⊝⊝ | |
| Nutritional status BMI Follow up: 12 ‐ 14 days | The mean change in BMI was 0.54 in the multiple‐daily dosing group. | The mean change in BMI was the same (0.42 higher to 0.42 lower) in the once‐daily dosing group. | NA | 41 (1 studies) | ⊕⊕⊝⊝ | There were also no statistically significant differences in mean change in weight/height percentage, MD ‐0.82 (95% CI ‐3.77 to 2.13), 22 participants, 1 study. |
| Time to first exacerbation requiring intravenous antibiotics Follow up: 12 months | The median time to next course of intravenous antibiotics was 168 days (95% CI 34 days to 302 days) in the multiple‐daily dosing group. | The median time to next course of intravenous antibiotics was 131 days (95% CI 76 days to 186 days) in the once‐daily dosing group. | NA | 113 (1 study) | ⊕⊕⊕⊝ | There was no statistically significant difference between treatment groups (P = 0.48). |
| Antibiotic resistance patterns following treatment Follow up: NA | Outcome not reported. | NA | ||||
| Ototoxicity An increase in auditory threshold of 20 dB or more over any frequency range Follow up: 12 ‐ 14 days | 8 per 1000 | 4 per 1000 (0 to 61 per 1000) | RR: 0.56 (0.04, 7.96) | 266 (3 studies) | ⊕⊕⊝⊝ | An additional study was not included in analysis due to the cross‐over design; there was no evidence of ototoxicity in any individual in this study. |
| Nephrotoxicity The percentage change in creatinine over baseline Follow up: 12 ‐ 14 days | The mean percentage change in creatine over baseline ranged from ‐1.1% lower to 3.7% higher in the multiple‐daily dosing group. | The mean percentage change in creatine over baseline was 0.61% lower (4.74% lower to 3.52% higher) in the once‐daily dosing group. | NA | 245 (3 studies) | ⊕⊕⊕⊝ | There was a statistically significant difference in subgroup analysis of studies recruiting adults and children; adults MD 3.25 (95% CI ‐1.82 to 8.33) and children MD ‐8.20 (95% CI ‐15.32 to ‐1.08). An additional study was not included in analysis due to the cross‐over design; there no statistically significant difference between treatment groups in this study. |
| *The basis for the assumed risk is the mean control group risk across studies or the event rate in the control group (as appropriate). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CI: confidence interval; FEV1 : forced expiratory volume in one second; FVC: forced vital capacity; MD: mean difference; NA: not applicable; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Multiple‐daily dosing was thrice daily dosing in all three studies contributing to analysis (Smyth 2005; Vic 1998; Whitehead 2002). 2. Downgraded once due to risk of bias: two studies were unblinded (Vic 1998; Whitehead 2002) and one study had incomplete outcome data (Whitehead 2002). 3. Downgraded once due to applicability: evidence only contributed by studies recruiting adults; results not applicable to children 4. Downgraded once due to applicability: evidence only contributed by one study recruiting children; results not applicable to adults 5. Downgraded once due to imprecision: wide confidence interval due to small number of events in both treatment groups. | ||||||
Background
Description of the condition
Cystic fibrosis (CF) is the most common serious autosomal recessive genetic disorder in the Caucasian population. It is estimated to occur in 1 in 2500 births and about one person in 25 carries the defective gene. Progressive pulmonary deterioration is the principal cause of CF‐related mortality and morbidity. People with CF have an increased susceptibility to chronic lung infections, especially withPseudomonas aeruginosa (P aeruginosa) (Davis 1996). Most antibiotics used for treatment are administered intravenously and given for about two weeks (David 1986); however, in a recent retrospective study nearly one third of individuals who were treated with more than 14 days of antibiotics showed improvements in lung function beyond the antibiotic treatment period, particularly in those who had greater decreases in forced expiratory volume in one second (FEV1) at the time of exacerbations, and in those who were slower to initially respond to treatment. Whether the improvements in lung function beyond the 14‐day period are associated with the antibiotic treatment or concurrent treatments, requires prospective study (Waters 2015).
Description of the intervention
People with CF receive frequent and repeated courses of intravenous antibiotics throughout their lifetime. The quality of evidence comparing intravenous antibiotics with placebo is poor. A recent Cochrane review concluded that no specific antibiotic combination can be considered to be superior to any other, and neither is there evidence showing that the intravenous route is superior to the inhaled or oral routes (Hurley 2015). The current recommendation for intravenous antibiotic treatment of pulmonary exacerbations in people colonised with P aeruginosa is a combination of two antibiotics with different mechanisms of action (CF Trust 2009; Flume 2009). Combination antibiotic therapy, which has been shown to produce a synergistic effect in vitro (Weiss 1995), may limit the emergence of antibiotic‐resistant strains of P aeruginosa (Cheng 1996). However, single versus combination intravenous antibiotic therapy in CF is the subject of another Cochrane Review which found no clear evidence of benefit for combination therapy, though there was a trend to less antibiotic resistance (Elphick 2005). Previously, the majority of people with CF received an aminoglycoside, as part of their intravenous antibiotic regimen, most commonly given in three divided doses (Tan 2002). However, a recent survey of prescribing practices in the UK has shown that a once‐daily regimen is usual practice in 86% of UK CF centres (Smyth 2014b).
How the intervention might work
Aminoglycosides demonstrate concentration dependent killing and the post‐antibiotic effect (Spivey 1992). Concentration‐dependent killing means that the bactericidal action of aminoglycosides is related to the peak concentration of antibiotic achieved. Greater bactericidal effect occurs at concentrations exceeding the minimum inhibitory concentration (MIC). The post‐antibiotic effect is a phenomenon in which the bactericidal action of the aminoglycoside continues even after the antibiotic has been cleared and its concentration has fallen below the MIC.
These pharmacological properties suggest that aminoglycosides could be given in higher concentrations with an extended dosing interval. There have been many randomised controlled trials (RCTs) comparing once‐daily with thrice‐daily aminoglycoside treatment in participants without CF and these have been the subject of a meta‐analysis (Barza 1996). This study reports that once‐daily dosing is as effective, and perhaps safer, than the standard thrice‐daily dosing regimen. However, the results of these studies cannot be directly extrapolated to the CF population, as plasma clearance is more rapid in people with CF (de Groot 1987). Furthermore, people with CF are vulnerable to cumulative side effects from antibiotics as they receive recurrent and prolonged courses of treatment.
Why it is important to do this review
The use of intravenous aminoglycosides is limited by their well‐recognised toxicity, affecting the inner ear and the kidney. Before any change in dosing interval can be recommended, the relative toxicity of once and multiple‐daily dosing must be evaluated.
Once‐daily aminoglycoside dosing has major advantages to people with CF and their families, especially if they receive their antibiotics at home. In addition there are cost implications in reducing the use of consumables and the time taken to prepare and deliver antibiotics.
This is an updated version of the previously published review (Smyth 2000; Smyth 2006; Smyth 2010; Smyth 2012; Smyth 2014a; Smyth 2017).
Objectives
To assess the efficacy and safety of once‐daily versus multiple‐daily intravenous aminoglycoside dosing in the treatment of pulmonary exacerbations in CF. The hypotheses will be tested that once‐daily intravenous aminoglycoside dosing is:
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as effective as multiple‐daily dosing (as measured by the change in lung function over a course of antibiotic treatment);
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no more toxic than multiple‐daily dosing (as measured by renal and auditory toxicity).
Methods
Criteria for considering studies for this review
Types of studies
RCTs, whether published or unpublished, and of parallel or cross‐over design. Studies using inappropriate forms of randomisation, such as alternate allocation, will not be considered. Where it is not clear, from the paper or the abstract, whether participants have been randomised appropriately, the authors will be contacted directly.
Types of participants
People with CF, who have been diagnosed by sweat test or genetic testing or both, regardless of age or clinical severity.
Types of interventions
Once‐daily dosing compared to multiple‐daily dosing of intravenous aminoglycoside antibiotics for pulmonary exacerbations in CF.
Types of outcome measures
Primary outcomes
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Lung function measurements
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forced expiratory volume in one second (FEV1)
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forced vital capacity (FVC)
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forced expiratory flow in mid expiration (FEF25‐75%)
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We compared the change in values from the start of antibiotic treatment with those taken at the end of treatment.
Secondary outcomes
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Nutritional status
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weight gain
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body mass index (BMI)
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z scores
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Time to first exacerbation requiring intravenous antibiotics*
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Antibiotic resistance patterns following treatment
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Ototoxicity (defined as an increase in auditory threshold of 20 dB or more over any frequency range)
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Nephrotoxicity (comparison of the percentage change in creatinine over baseline)
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Possible adverse events associated with aminoglycoside infusion (e.g. vestibular changes, tinnitus, anaphylaxis)
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Quality of life measures (if well‐validated scores are available e.g. Cystic Fibrosis Quality of Life ‐ Revised (CFQ‐R) (Quittner 2009))
*Where possible, a pulmonary exacerbation will be defined as four or more of the following 12 symptoms or signs: change in sputum; new or increased haemoptysis; increased cough; increased dyspnoea; malaise, fatigue or lethargy; temperature above 38º C; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10% or more from a previously recorded value; radiographic changes indicative of a pulmonary infection (Fuchs 1994). Where there is no such definition of an exacerbation we will use the definition provided in the study report.
Search methods for identification of studies
No language or publication status restrictions were imposed in the process of identifying studies.
Electronic searches
Relevant studies were identified from the Group's Cystic Fibrosis Trials Register using the terms: (intravenous OR *stated) AND (tobramycin OR amikacin OR gentamicin OR netilmicin OR sisomicin OR neomycin).
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 through 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's website.
Date of the most recent search of the Group's CF Trials Register: 31 January 2019.
Authors also searched online study registries (WHO ICTRP and clinicaltrials.gov) for relevant ongoing studies using the search terms: 'cystic fibrosis' AND 'aminoglycoside'. Date of latest search: 25 February 2019.
Data collection and analysis
Selection of studies
Two authors independently selected studies for inclusion in the review. We resolved any disagreements by negotiation.
Data extraction and management
Two authors independently extracted data and resolved any disagreements by negotiation. We collected data for the outcome events listed above.
Assessment of risk of bias in included studies
Two authors assessed the risk of bias in the included studies by following the domain‐based assessment as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the following domains:
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sequence generation;
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allocation concealment;
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blinding (if it took place and who was blinded);
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incomplete outcome data;
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selective reporting;
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other sources of bias.
On the basis of these assessments, we attributed a high or low or unclear risk of bias for each domain to each study. For example, if the randomisation sequence was generated using random number tables or a computer, we judged there to be a low risk of bias for this domain.
Measures of treatment effect
For dichotomous variables (such as adverse events) we used risk ratios (RR) and 95% confidence intervals (CIs) and calculated a pooled estimate of treatment effect across all studies. For continuous variables, such as lung function, we pooled the treatment effect across all studies, using the mean difference (MD) and 95% CIs.
Unit of analysis issues
We planned to analyse cross‐over studies using the results from paired analysis where possible. We intended to use estimates of treatment effect and standard errors (or equivalent) from the study report, or (if not available) we planned to contact the study authors (Elbourne 2002). We have included two cross‐over studies, but we were unable to obtain these data and so we have described the results in narrative form (Al Ansari 2006; Riethmueller 2009).
Dealing with missing data
If data were missing, we attempted to contact the study investigators for clarification.
Assessment of heterogeneity
When sufficient studies are included in the review, we will test for heterogeneity between study results using the I² statistic (Higgins 2003). This measure describes the percentage of the variability in effect estimates that is due to heterogeneity rather than chance. We plan to use the following interpretation of the statistic:
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0% to 40%: might not be important;
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30% to 60%: may represent moderate heterogeneity;
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50% to 90%: may represent substantial heterogeneity;
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75% to 100%: considerable heterogeneity.
Assessment of reporting biases
We planned to compare original study protocols to final published papers to identify any selective reporting. If the original study protocols were not available, we examined the final published papers to identify any outcomes stated as being measured, but not reported in the study results.
We planned to assess publication bias by visual inspection of funnel plots, if we had been able to include and combine at least 10 studies.
Data synthesis
We have analysed the included data using a fixed‐effect model. If investigation of the studies indicates an at least substantial level of heterogeneity (over 50% using the I² statistic) among those included in an analysis, we will use a random‐effects model.
Subgroup analysis and investigation of heterogeneity
Furthermore, if we identify a substantial or considerable level of heterogeneity (as defined above) and have included sufficient studies in the review, we will perform subgroup analysis, looking at the pre‐defined subgroups of children versus adults.
Sensitivity analysis
We will undertake a sensitivity analysis if there is risk of small study effects and if they have included sufficient studies in the review.
Summary of findings and quality of the evidence (GRADE)
In a post hoc change from protocol, we have presented a summary of findings table for the comparison of once‐daily versus multiple‐daily dosing with intravenous aminoglycosides in people with CF (summary of findings Table for the main comparison)
We reported the following outcomes in the tables (chosen based on relevance to clinicians and consumers) ‐ lung function (change in percent (%) predicted FEV1 and FVC), nutritional status (BMI), time to first exacerbation requiring intravenous antibiotics, antibiotic resistance, ototoxicity and nephrotoxicity.
We determined the quality of the evidence using the GRADE approach; and downgraded evidence in the presence of a high risk of bias in at least one study, indirectness of the evidence, unexplained heterogeneity or inconsistency, imprecision of results, high probability of publication bias. We downgraded evidence by one level if they considered the limitation to be serious and by two levels if very serious.
Results
Description of studies
Results of the search
The searches identified 16 studies. Five studies were included in the review and 11 studies were excluded from the review.
Please see the PRISMA diagram illustrating the flow of studies in the review process (Figure 1).
Study flow diagram.
Included studies
Five studies, with a total of 354 participants completing treatment per protocol, fulfilled the inclusion criteria for this review (RCTs, whether published or unpublished, and of parallel or cross‐over design) (Al Ansari 2006; Riethmueller 2009; Smyth 2005; Vic 1998; Whitehead 2002).
Methods
Two studies were cross‐over in design (Al Ansari 2006; Riethmueller 2009); one did not specify any washout period (Al Ansari 2006) and one reported a three‐month washout period (Riethmueller 2009). The remaining three studies were of parallel design (Smyth 2005; Vic 1998; Whitehead 2002). Four studies were unblinded (Al Ansari 2006; Riethmueller 2009; Vic 1998; Whitehead 2002) and one was double‐blind (Smyth 2005). Data were recorded at the end of the treatment course which was 14 days in three studies (Riethmueller 2009; Smyth 2005; Vic 1998) and 12 days in one study (Whitehead 2002). In one study, microbiological changes were reported at 14 days but clinical response at day 7 only (Al Ansari 2006). No study reported longer‐term outcomes. As the Smyth study was an equivalence study, the analysis was per protocol (Smyth 2005).
Participants
The number of participants in each study ranged from 22 (Vic 1998) to 244 (219 of whom completed the study per protocol) (Smyth 2005). Two studies recruited only adults with an age range of 15 years to 47 years (Al Ansari 2006; Whitehead 2002) and one study recruited paediatric participants with a mean age of 11.2 years and a range from 1.7 years to 18.1 years (Riethmueller 2009). The remaining two studies recruited a mixture of children and adults, age range 5.6 years to 19.3 years (Vic 1998) and 5.1 years to 50.4 years (Smyth 2005). There were slightly more males than females in two studies (131 out of 219 (Smyth 2005) and 14 out of 22 (Vic 1998)) and more females than males in two studies (20 out of 30 (Riethmueller 2009) and 33 out of 60 (Whitehead 2002)).
Riethmueller reported that three out of the eight participants lost to follow‐up were found to be colonized with resistant P aeruginosa strains and were therefore switched from ceftazidime to meropenem (Riethmueller 2009).
Interventions
All four studies evaluated the efficacy and toxicity of once versus thrice‐daily dosing of intravenous tobramycin for a pulmonary exacerbation. No studies were found, which compared once‐daily aminoglycoside dosing with any other frequency of dosing. One study additionally evaluated the use of continuous ceftazidime infusions, which is beyond the remit of this review (Riethmueller 2009).
The total daily dose of tobramycin in each group was 15 mg/kg/day in one study (Vic 1998) and 10 mg/kg/day in the remaining four studies (Al Ansari 2006; Riethmueller 2009; Smyth 2005; Whitehead 2002). In two studies, tobramycin was given in combination with ceftazidime 200 mg/kg/day (Riethmueller 2009; Vic 1998) and in a third study tobramycin was combined with ceftazidime 150 mg/kg/day in three divided doses (Smyth 2005). Whitehead administered tobramycin in combination with a beta‐lactam antibiotic, chosen by the clinician (either piperacillin, piperacillin/tazobactam, aztreonam, azlocillin, imipenem, meropenem or ceftazidime) (Whitehead 2002). One study allowed the clinician to select ceftazidime, meropenem, aztreonam, or ciprofloxacin as the second antibiotic (Al Ansari 2006).
Outcomes
All five studies reported on lung function using FEV1 (Al Ansari 2006; Riethmueller 2009; Smyth 2005; Vic 1998; Whitehead 2002) and four using FVC (Riethmueller 2009; Smyth 2005; Vic 1998; Whitehead 2002); one study additionally reported FEF25‐75% (Whitehead 2002). One study reported FEV1 after 7 days and not at the end of the 14 day course; furthermore this study did not report first‐arm outcomes for the 26 participants randomised (Al Ansari 2006). Ototoxicity and nephrotoxicity were also reported by all included studies (Riethmueller 2009; Smyth 2005; Vic 1998; Whitehead 2002). One study asked about symptoms of but did not measure ototoxicity (Al Ansari 2006). Four studies also reported some measure of nutritional status, although the unit of measurement varied ‐ two studies reported weight in kg (Riethmueller 2009; Smyth 2005), one study reported BMI (Whitehead 2002) and the fourth study reported weight/height % (Vic 1998). One study measured but did not report nutritional outcomes (Al Ansari 2006). Three studies reported on changes in inflammatory markers (Smyth 2005; Vic 1998; Whitehead 2002). One study additionally reported participant preference of treatment regimens, clinical score and white cell count (% neutrophils) (Whitehead 2002). A further study also reported the time to next intravenous antibiotics and attempted to interpret changes in the antibiotic resistance patterns of P. aeruginosa, but there were insufficient data to do this (Smyth 2005). One study reported minimum inhibitory concentration of P aeruginosa to tobramycin at baseline, 7 and 14 days as well as total viable bacterial count at these time points (Al Ansari 2006).
Excluded studies
As detailed in the tables, 11 studies were excluded (Characteristics of excluded studies). Three studies were pharmacokinetic papers (Aminimanizani 2002; Burkhardt 2006; Hamner 2006); one study used alternate allocation of treatment (Heininger 1993); one study compared monotherapy to combination therapy (Master 2001); one study was not blinded and measured efficacy on a symptom score (Powell 1983); for one study (published as an abstract) no outcome data were available and it was not clear whether the participants were randomised (Postnikov 2007); one did not include a once‐daily arm of treatment (Adeboyeku 2011); the remaining two studies did not compare once‐daily dosing with another dosing schedule (Winnie 1991; Wood 1996). One USA‐based multicentre RCT of once daily or thrice daily with tobramycin (12 mg/kg/day) plus the usual beta‐lactam which was previously listed as ongoing in this review, but the study failed to recruit a sufficient number of participants and was terminated without any data being made available (Tureen 2001).
Risk of bias in included studies
Allocation
In one study the randomisation schedule was generated using a computer and stratified by centre and adult versus paediatric (Smyth 2005). In two studies randomisation tables were used (Vic 1998; Whitehead 2002). All three of these studies were judged to have a low risk of bias from the generation of the randomisation sequence (Smyth 2005; Vic 1998; Whitehead 2002). The fourth study was described as randomised; it was a six‐centre study in which three centres randomised with three protocols and three centres randomised with two protocols, but no actual details of the randomisation process were given, so this study was therefore judged to have an unclear risk of bias (Riethmueller 2009). The method of randomisation was also not described in the final study and so this also had an unclear risk of bias (Al Ansari 2006).
In one study, central randomisation was used and the study was judged to have a low risk of bias for allocation concealment (Smyth 2005). Allocation concealment was not clear from the published account in four of the studies, hence there was an unclear risk of bias for these studies (Al Ansari 2006; Riethmueller 2009; Vic 1998; Whitehead 2002). Of note, one study was a six‐centre study in which three centres randomised with three protocols and three centres randomised with two protocols (Riethmueller 2009).
Blinding
Only one study used a masked placebo and thus was judged to have a low risk of bias (Smyth 2005). Four of the five studies were unblinded to treatment regimen and so had a high risk of bias (Al Ansari 2006; Riethmueller 2009; Vic 1998; Whitehead 2002).
Incomplete outcome data
We contacted the authors of the Vic study, who informed us that no participants withdrew or were withdrawn from the study, leading to a low risk of bias (Vic 1998). A per‐protocol analysis was performed as the primary analysis in another study as this was an equivalence study (Smyth 2005). This is the appropriate methodology for an equivalence study and does not increase risk of bias. Intention‐to‐treat analysis was not performed in two studies (Riethmueller 2009; Whitehead 2002). In the Riethmueller study there is an unclear risk of bias as a per‐protocol analysis was performed of 30 of 38 participants (Riethmueller 2009). Likewise, in the Whitehead study there is an unclear risk of bias as only 49 participants were studied out of the 60 who were recruited and there is no further information on the remaining 11 participants (Whitehead 2002). The final study recruited 26 participants but reported data on 15 participants only (no first‐arm data available) and we deemed this high risk of bias (Al Ansari 2006).
Selective reporting
We were able to compare one study with its previously published protocol and we found no evidence of selective reporting and hence judged this study to have a low risk of bias (Smyth 2005). We were unable to compare any protocols to final publications for any of the other included studies. We judge there to be an unclear risk of bias from selective reporting in three studies (Riethmueller 2009; Vic 1998; Whitehead 2002). Additionally, the fourth study without a published protocol, measured but did not report weight and creatinine; we judged this high risk of bias (Al Ansari 2006).
Other potential sources of bias
We were not able to identify any other potential source of bias in the included studies.
Effects of interventions
See: Summary of findings for the main comparison
For each outcome measure, the number of participants differed due to incomplete data. Meta‐analysis of pooled data was not possible for the outcome measures looking at nutritional status.
The evidence grades stated for the outcomes reported in the Summary of Findings table are based on GRADE (Data collection and analysis) and further details are provided in the Summary of Findings table (summary of findings Table for the main comparison).
Primary outcomes
1. Lung function
a. Mean percentage change in FEV1
This outcome was reported in three studies with a total of 289 participants (Smyth 2005; Vic 1998; Whitehead 2002). The MD for the change in FEV1 (% predicted) was 0.33 (95% CI ‐2.81 to 3.48) (moderate‐quality evidence) (Analysis 1.1). There was no significant difference between antibiotic regimens in the increment in FEV1 seen with antibiotic treatment. One study did not report FEV1 (% predicted) at the end of the 14‐day course (Al Ansari 2006).
b. Mean percentage change in FVC
This outcome was reported in two studies with a total of 70 participants (Vic 1998; Whitehead 2002). There was no significant difference between antibiotic regimens in the increment in FVC (% predicted) seen after treatment. The MD for change in FVC (% predicted) was 0.29 (95% CI ‐6.58 to 7.16) (low‐quality evidence) (Analysis 1.2).
c. Mean percentage change in FEF25‐50%
This outcome was only reported in one study with 48 participants (Whitehead 2002). Again there was no difference between regimens. The MD for change in FEF25‐50 (% predicted) was ‐1.24 (95% CI ‐7.78 to 5.30) (Analysis 1.3).
Secondary outcomes
1. Nutritional status
The mean change in weight/height percentage was assessed in one study with 22 participants (Vic 1998). The MD for this outcome was ‐0.82 (95% CI ‐3.77 to 2.13), which suggests that the mean increase in weight/height percentage was similar in both the once‐daily and thrice‐daily groups (Analysis 1.4).
The mean change in BMI was assessed in one study with 41 participants (Whitehead 2002). The MD for the mean change in BMI was 0.00 (95% CI ‐0.42 to 0.42) (low‐quality evidence), this suggests that the mean increase in BMI was similar in both the once‐daily and thrice‐daily groups (Analysis 1.5).
2. Time to first exacerbation (requiring intravenous antibiotics) after treatment
Data were available from one study for the time to next course of intravenous antibiotics for 113 participants (56 on once daily, 57 on thrice daily) (Smyth 2005). The median time was 131 days (95% CI 76 days to 186 days) for once daily and 168 days (95% CI 34 days to 302 days) for three‐times daily treatment (P = 0·48) (moderate‐quality evidence).
3. Resistance patterns following treatment
This was reported in one study, though no statistical comparison was made (Al Ansari 2006).
4. Ototoxicity
The investigators in the Riethmueller study performed audiograms in all participants after treatment and found no evidence of ototoxicity in any individual (Riethmueller 2009). Audiograms were also performed in the Vic study and the results were reported, but did not show any instances of ototoxicity (Vic 1998). In the Whitehead study, one participant in each group was reported as experiencing ototoxicity (Whitehead 2002). In the Smyth study 168 out of 219 participants who completed treatment per protocol had audiograms performed at the start and finish of their intravenous antibiotic course; no participant showed deterioration in audiograms from days 1 to 14 of treatment (Smyth 2005). Two participants (one on each regimen) reported acute dizziness and were withdrawn from the study. In both participants, symptoms resolved without treatment. Therefore, there was no significant difference in the relative risk of developing ototoxicity between once and thrice‐daily dosing in the four studies considered, RR 0.56 (95% CI 0.04 to 7.96) (low‐quality evidence) (Analysis 1.6).
Furthermore, in the TOPIC study 69 participants had a follow‐up audiogram between six and eight weeks after the end of treatment; there were no significant differences between the audiograms and no difference between regimens (Mulheran 2006).
One study reported no toxicity in study participants, but describes one participant withdrawing from the second arm of treatment because of dizziness (Al Ansari 2006).
5. Nephrotoxicity
The measure of nephrotoxicity, which was pre‐defined in the protocol, was the percentage increase in serum creatinine from baseline.
One study measured but did not report serum creatinine (Al Ansari 2006).
Two studies reported nephrotoxicity as pre‐defined (Smyth 2005; Whitehead 2002). When data from the two studies were combined, there was a non‐significant trend towards a greater rise in creatinine with once‐daily treatment in adults, MD 3.25 (95% CI ‐1.82 to 8.33) (Analysis 1.7). In contrast, data from one study showed that in children there was a significantly smaller rise in creatinine with once‐daily treatment, MD ‐8.20 (95% CI ‐15.32 to ‐1.08) (moderate‐quality evidence) (Analysis 1.7). Two studies measured N‐acetyl‐β‐D glucosaminidase (NAG), a proximal tubular enzyme (Smyth 2005; Riethmueller 2009). This was measured at baseline and after 14 days of treatment in both studies. A significantly smaller rise (less toxicity) was seen with once daily for adults and children combined in the Smyth study (Smyth 2005). Riethmueller measured both urinary concentrations of NAG and α‐1‐microglobulin (Riethmueller 2009). Both increased significantly during treatment, but there was no difference between regimens. The Vic study used creatinine clearance, lysozymuria and microglobulinuria to assess nephrotoxicity; for microglobulinuria there was a difference between groups on day 14 in favour of once‐daily treatment (Vic 1998).
Therefore, using the pre‐defined outcome measure of percentage change in creatinine over baseline, there was a significant difference in favour of once‐daily treatment in children.
6. Adverse events associated with aminoglycoside infusion
None of the included studies reported this outcome.
7. Quality of life
None of the included studies reported this outcome.
Discussion
Summary of main results
We systematically reviewed available evidence comparing the effectiveness and toxicity for once‐daily dosing of aminoglycosides to multiple‐daily dosing. Five studies met the inclusion criteria for this review (a total of 354 participants contributed data). All studies used tobramycin as the aminoglycoside of choice, dosed at either 10 mg/kg/day or 15 mg/kg/day or the dose last known to give satisfactory levels. In all studies, once‐daily dosing was compared with thrice‐daily dosing. Whilst the three studies used the same combination of antibiotics for all participants (Riethmueller 2009; Smyth 2005; Vic 1998), two used a selection of anti‐pseudomonal antibiotics in combination with tobramycin (Al Ansari 2006; Whitehead 2002). Therefore, the individual effects of other classes of antibiotic in this study are unknown.
This systematic review has demonstrated no significant difference in efficacy, measured by improvement in lung function (moderate‐ to low‐quality evidence), between once‐daily and thrice‐daily dosing of tobramycin. The combined number of participants (289) for the outcome measure of lung function, as measured by FEV1, give sufficient statistical power to demonstrate a true difference between regimens of 4% predicted, if one were present. However, evidence of no greater risk of toxicity between once‐daily and thrice‐daily dosing is encouraging. This systematic review has shown that the relative risk of developing ototoxicity between the two treatment groups was not significant (low‐quality evidence). However, the results of studies of nephrotoxicity suggested that the rise in creatinine was significantly less in children with once‐daily treatment (moderate‐quality evidence). In adults the effect was in favour of three‐times daily treatment, but was not significant. The magnitude of the change in creatinine was much less than the threshold for clinical renal impairment but could be clinically important, if the effect were cumulative with subsequent courses of treatment.
Finally, in a chronic disorder such as CF, long‐term measures of health status are important. There was no difference found in time to next exacerbation in one study (Smyth 2005). Any differences in long‐term benefits of improved lung function and nutritional status between the two groups is unknown.
Overall completeness and applicability of evidence
In each of the five studies included in this review the chosen aminoglycoside was tobramycin. There are several antibiotics in this class which are used in clinical practice. However gentamicin, which is widely used for the management of other infections in children and adults, is associated with increased toxicity in CF (Smyth 2008). Treatment guidelines from the UK CF Trust recommend that gentamicin should not be used (CF Trust 2009). Once‐ versus multiple‐daily dosing has not been evaluated for other aminoglycosides such as amikacin, which is indicated for the management of pulmonary infection with non‐tuberculous mycobacteria in CF (Floto 2016) ‐ a problem which is increasingly prevalent in people with CF. There are limited data on the long‐term effects of different aminoglycoside dosing regimens on toxicity to hearing or renal function and on other outcomes such as antibiotic resistance.
Quality of the evidence
When comparing once‐daily and multiple‐daily dosing, the expectation may be that the new treatment (once‐daily dosing) is better than the standard (thrice‐daily dosing). In fact, it is more likely that the new treatment will match the efficacy of the standard treatment, but have advantages perhaps in safety, convenience and cost. Therefore, the most useful comparison of once‐daily and multiple‐daily dosing is one using the methodology for an equivalence study, as suggested in a paper by Jones (Jones 1996). The TOPIC study employed this study design (Smyth 2005), as did the study by Whitehead (Whitehead 2002). The largest study included in this review was judged to have signed a low risk for all forms of bias (Smyth 2005). The remaining studies did not describe allocation concealment, were not blinded and did not perform an intention‐to‐treat analysis (Al Ansari 2006; Riethmueller 2009; Vic 1998; Whitehead 2002).
With regards to the assessment of the quality of evidence presented in the summary of findings table, we graded the evidence as moderate quality for most outcomes (there was a risk of bias in two of the included studies) and low quality where the results are not applicable to a particular section of the population (either adults or children).
Potential biases in the review process
The lead author of this review (AS) was chief investigator for the TOPIC study, which is the largest study included in this review (Smyth 2005). The risk of bias judgements were made by the remaining two authors.
Agreements and disagreements with other studies or reviews
This is the only systematic review to compare once with multiple‐daily dosing of aminoglycosides in people with CF. However, our findings are in agreement with a meta‐analysis which looked at the same comparison in people treated with aminoglycosides for a variety of infections (Barza 1996).
Comparison 1 Once‐daily dosing of intravenous aminoglycoside antibiotics versus multiple‐daily dosing, Outcome 1 Mean percentage change in FEV1 (% predicted).
Comparison 1 Once‐daily dosing of intravenous aminoglycoside antibiotics versus multiple‐daily dosing, Outcome 2 Mean percentage change in FVC (% predicted).
Comparison 1 Once‐daily dosing of intravenous aminoglycoside antibiotics versus multiple‐daily dosing, Outcome 3 Mean change in FEF25‐75 (% predicted).
Comparison 1 Once‐daily dosing of intravenous aminoglycoside antibiotics versus multiple‐daily dosing, Outcome 4 Mean change in weight/height %.
Comparison 1 Once‐daily dosing of intravenous aminoglycoside antibiotics versus multiple‐daily dosing, Outcome 5 Mean change in BMI.
Comparison 1 Once‐daily dosing of intravenous aminoglycoside antibiotics versus multiple‐daily dosing, Outcome 6 Development of ototoxicity (after treatment).
Comparison 1 Once‐daily dosing of intravenous aminoglycoside antibiotics versus multiple‐daily dosing, Outcome 7 Percentage change in creatinine with treatment.
| Once‐daily compared with multiple‐daily dosing with intravenous aminoglycosides for cystic fibrosis | ||||||
| Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: once‐daily dosing of intravenous aminoglycosides Comparison: multiple‐daily dosing of intravenous aminoglycosides | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Multiple‐daily dosing of intravenous aminoglycosides1 | Once‐daily dosing of intravenous aminoglycosides | |||||
| Lung function Mean percentage change in FEV1 Follow up: 12 ‐ 14 days | The mean percentage change in FEV1 (% predicted) ranged between 9.66 and 14.9 in the multiple‐daily dosing groups. | The mean percentage change in FEV1 (% predicted) was 0.33 higher (2.81 lower to 3.48 higher) in the once‐daily dosing groups. | NA | 289 | ⊕⊕⊕⊝ | |
| Lung function Mean percentage change in FVC (% predicted) Follow up: 12 ‐ 14 days | The mean percentage change in FVC (% predicted) ranged between 12.2 and 13.8 in the multiple‐daily dosing groups. | The mean percentage change in FVC (% predicted) was 0.29 higher (6.58 lower to 7.16 higher) in the once‐daily dosing groups. | NA | 70 (2 studies) | ⊕⊕⊝⊝ | |
| Nutritional status BMI Follow up: 12 ‐ 14 days | The mean change in BMI was 0.54 in the multiple‐daily dosing group. | The mean change in BMI was the same (0.42 higher to 0.42 lower) in the once‐daily dosing group. | NA | 41 (1 studies) | ⊕⊕⊝⊝ | There were also no statistically significant differences in mean change in weight/height percentage, MD ‐0.82 (95% CI ‐3.77 to 2.13), 22 participants, 1 study. |
| Time to first exacerbation requiring intravenous antibiotics Follow up: 12 months | The median time to next course of intravenous antibiotics was 168 days (95% CI 34 days to 302 days) in the multiple‐daily dosing group. | The median time to next course of intravenous antibiotics was 131 days (95% CI 76 days to 186 days) in the once‐daily dosing group. | NA | 113 (1 study) | ⊕⊕⊕⊝ | There was no statistically significant difference between treatment groups (P = 0.48). |
| Antibiotic resistance patterns following treatment Follow up: NA | Outcome not reported. | NA | ||||
| Ototoxicity An increase in auditory threshold of 20 dB or more over any frequency range Follow up: 12 ‐ 14 days | 8 per 1000 | 4 per 1000 (0 to 61 per 1000) | RR: 0.56 (0.04, 7.96) | 266 (3 studies) | ⊕⊕⊝⊝ | An additional study was not included in analysis due to the cross‐over design; there was no evidence of ototoxicity in any individual in this study. |
| Nephrotoxicity The percentage change in creatinine over baseline Follow up: 12 ‐ 14 days | The mean percentage change in creatine over baseline ranged from ‐1.1% lower to 3.7% higher in the multiple‐daily dosing group. | The mean percentage change in creatine over baseline was 0.61% lower (4.74% lower to 3.52% higher) in the once‐daily dosing group. | NA | 245 (3 studies) | ⊕⊕⊕⊝ | There was a statistically significant difference in subgroup analysis of studies recruiting adults and children; adults MD 3.25 (95% CI ‐1.82 to 8.33) and children MD ‐8.20 (95% CI ‐15.32 to ‐1.08). An additional study was not included in analysis due to the cross‐over design; there no statistically significant difference between treatment groups in this study. |
| *The basis for the assumed risk is the mean control group risk across studies or the event rate in the control group (as appropriate). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CI: confidence interval; FEV1 : forced expiratory volume in one second; FVC: forced vital capacity; MD: mean difference; NA: not applicable; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Multiple‐daily dosing was thrice daily dosing in all three studies contributing to analysis (Smyth 2005; Vic 1998; Whitehead 2002). 2. Downgraded once due to risk of bias: two studies were unblinded (Vic 1998; Whitehead 2002) and one study had incomplete outcome data (Whitehead 2002). 3. Downgraded once due to applicability: evidence only contributed by studies recruiting adults; results not applicable to children 4. Downgraded once due to applicability: evidence only contributed by one study recruiting children; results not applicable to adults 5. Downgraded once due to imprecision: wide confidence interval due to small number of events in both treatment groups. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage change in FEV1 (% predicted) Show forest plot | 3 | 289 | Mean Difference (IV, Fixed, 95% CI) | 0.33 [‐2.81, 3.48] |
| 2 Mean percentage change in FVC (% predicted) Show forest plot | 2 | 70 | Mean Difference (IV, Fixed, 95% CI) | 0.29 [‐6.58, 7.16] |
| 3 Mean change in FEF25‐75 (% predicted) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4 Mean change in weight/height % Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5 Mean change in BMI Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 6 Development of ototoxicity (after treatment) Show forest plot | 3 | 266 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.04, 7.96] |
| 7 Percentage change in creatinine with treatment Show forest plot | 2 | 245 | Mean Difference (IV, Fixed, 95% CI) | ‐0.61 [‐4.74, 3.52] |
| 7.1 Percentage change in creatinine with treatment ‐ adults | 2 | 131 | Mean Difference (IV, Fixed, 95% CI) | 3.25 [‐1.82, 8.33] |
| 7.2 Percentage change in creatinine with treatment ‐ children | 1 | 114 | Mean Difference (IV, Fixed, 95% CI) | ‐8.2 [‐15.32, ‐1.08] |
