Tratamiento intravenoso con antibióticos antipseudomonas solos versus combinados para personas con fibrosis quística
Resumen
Antecedentes
La elección del antibiótico y el uso de un tratamiento solo o combinado son temas controvertidos en el tratamiento de la infección respiratoria debida a Pseudomonas aeruginosa en la fibrosis quística (FQ). Entre las ventajas del tratamiento combinado figuran una mayor variedad de mecanismos de acción, la posible sinergia y la reducción de los microorganismos resistentes; entre las ventajas de la monoterapia figuran el menor coste, la facilidad de administración y la reducción de la toxicidad relacionada con los fármacos. La evidencia actual no proporciona una respuesta clara y el uso del tratamiento con antibióticos por vía intravenosa en la FQ requiere una evaluación más profunda. Ésta es una actualización de una revisión publicada anteriormente.
Objetivos
Evaluar la efectividad del tratamiento intravenoso con antibióticos antipseudomonas solos comparado con combinados para tratar a las personas con FQ.
Métodos de búsqueda
Se realizaron búsquedas en el registro de ensayos del Grupo Cochrane de Fibrosis quística y enfermedades genéticas (Cochrane Cystic Fibrosis and Genetic Disorders Group) que incluye referencias identificadas de búsquedas exhaustivas en bases de datos electrónicas o búsquedas manuales en revistas relevantes y libros de resúmenes de congresos.
Búsqueda más reciente en el registro de ensayos del Grupo: 7 de octubre de 2020.
También se hicieron búsquedas en registros de ensayos en línea el 16 de noviembre de 2020.
Criterios de selección
Ensayos controlados aleatorizados (ECA) que compararon un único antibiótico intravenoso antipseudomonas con una combinación de ese antibiótico más un segundo antibiótico antipseudomonas en personas con FQ.
Obtención y análisis de los datos
Dos autores de la revisión, de forma independiente, evaluaron la calidad de los ensayos y extrajeron los datos. La certeza de los datos se evaluó mediante el método GRADE.
Resultados principales
Se identificaron 59 ensayos, de los cuales se incluyeron ocho (356 participantes) que compararon un único agente antipseudomonas con una combinación del mismo antibiótico y otro más. Hubo una amplia variación entre los antibióticos individuales utilizados en cada ensayo. En total, los ensayos incluyeron siete comparaciones de un antibiótico betalactámico (relacionado con la penicilina o cefalosporina de tercera generación) con una combinación de betalactámico‐aminoglucósido y tres comparaciones de un aminoglucósido con una combinación de betalactámico‐aminoglucósido.
Hubo una considerable heterogeneidad entre estos ensayos, lo que provocó dificultades en la realización de la revisión y la interpretación de los resultados. Estos resultados se deben interpretar con cautela. Seis de los ensayos incluidos se publicaron entre 1977 y 1988 y fueron unicéntricos con deficiencias en el proceso de asignación al azar y un tamaño muestral pequeño. En general, la calidad metodológica fue deficiente y la certeza de la evidencia varió de baja a moderada.
La revisión no encontró diferencias entre la monoterapia y el tratamiento combinado, a corto y largo plazo, en los desenlaces de diferentes medidas de la función pulmonar, medidas de desenlaces bacteriológicos, necesidad de tratamiento adicional, efectos adversos, calidad de vida o puntuaciones de los síntomas.
Conclusiones de los autores
Los resultados de esta revisión no son concluyentes. La revisión plantea importantes problemas metodológicos. Se requiere de un ECA que deberá estar bien diseñado en cuanto a la asignación aleatoria, el cegamiento, la potencia estadístico y el seguimiento a largo plazo suficientes. Es necesario estandarizar los resultados con un método coherente de presentación de información, a fin de validar la agrupación de los resultados de múltiples ensayos.
PICO
Resumen en términos sencillos
Una comparación de tratamientos farmacológicos intravenosos solos y combinados para personas con fibrosis quística infectadas por Pseudomonas aeruginosa
Pregunta de la revisión
Se revisó la evidencia sobre los diferentes efectos del uso de un único antibiótico intravenoso (administrado directamente en una vena) en comparación con el uso de una combinación de antibióticos intravenosos en personas con fibrosis quística infectadas por Pseudomonas aeruginosa.
Antecedentes
La fibrosis quística es una enfermedad genética grave que afecta las células de las glándulas exocrinas (glándulas del sudor y otras). Las personas con fibrosis quística tienen un mayor riesgo de infecciones pulmonares crónicas, a menudo debido a la bacteria llamada Pseudomonas aeruginosa. Estas personas reciben antibióticos, ya sea un medicamento solo o una combinación de varios, administrados en vena para tratar estas infecciones. La elección del antibiótico y el uso de tratamiento solo o combinado varían. Se buscaron ensayos controlados aleatorizados que compararan un único antibiótico intravenoso con una combinación de ese antibiótico más otro en personas con fibrosis quística. Esta es una versión actualizada de la revisión.
Fecha de la búsqueda
La evidencia está actualizada hasta el: 7 de octubre de 2020.
Características de los estudios
Se incluyeron ocho ensayos con un total de 356 participantes. Seis de ellos se publicaron antes de 1988, cada uno se realizó en un solo centro y utilizaron una serie de medicamentos diferentes. Estos factores dificultaron la combinación y el análisis de los resultados.
Resultados clave
No se encontraron diferencias entre los dos tratamientos en cuanto a la función pulmonar, los desenlaces bacteriológicos, los efectos secundarios ni las puntuaciones de los síntomas. Se considera que no existe suficiente evidencia para comparar adecuadamente los diferentes tratamientos. Se necesitan más estudios de investigación, en concreto sobre los efectos secundarios del tratamiento.
Calidad de la evidencia
Se consideró que la certeza de la evidencia era de baja a moderada. Seis de los ensayos incluidos eran bastante antiguos (se publicaron entre 1977 y 1988). No incluían a muchas personas y tenían deficiencias en la forma en que las personas que participaron se asignaron a los diferentes grupos de tratamiento. En general, la calidad del diseño de los ensayos fue deficiente.
Authors' conclusions
Summary of findings
| Single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ short‐term effects | ||||||
| Patient or population: children and adults with cystic fibrosis Settings: inpatient or outpatient Intervention: combination IV antibiotic therapy Comparison: single IV antibiotic | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Single IV antibiotic therapy | Combined IV antibiotic therapy | |||||
| Change in FEV1 % predicted at end of antibiotic course: absolute post‐treatment values
Follow‐up: 10 ‐ 14 days | The mean FEV1 (% predicted) ranged across control groups from | The mean FEV1 (% predicted) in the intervention groups was | MD 5.25 (95% CI ‐9.14 to 19.64) | 93 | ⊕⊕⊝⊝
| 3 further trials reported on this outcome, but it was not possible to include the data in our analyses. Master reported that the combination antibiotic group had a significantly higher FEV1 % predicted after 10 days of treatment (P < 0.05) (Master 1997). McCarty reported a "similar improvement" in FEV1 in both groups but no further detail (McCarty 1988). The elective trial reported higher median values for FEV1 % predicted in the combination group at baseline and Day 14, but at Day 90 the median was higher in the single antibiotic group (Pedersen 1986). |
| Change in sputum P aeruginosa density at end of treatment (cfu/g)
Follow‐up: 10 ‐ 14 days | The mean (SD) sputum P aeruginosa density was 6.9 cfu/g (15.5) in the control group. | The mean sputum P aeruginosa density in the intervention groups was | MD ‐1.60 cfu/g (95% CI ‐9.51 to 6.31) | 76 | ⊕⊕⊕⊝
| 2 further trials looked at bacterial concentration, but used different measures and reported within‐group differences only. McLaughlin reported a significant decrease in bacterial concentration (cfu/mL) in the combination group and a non‐significant decrease in the single antibiotic group (McLaughlin 1983). McCarty reported 5/19 P aeruginosa isolates in the single therapy group decreased in titre by more than 10² cfu/mL compared to 12/19 P aeruginosa isolates in the combination group (McCarty 1988). |
| Additional treatment required
| This outcome was not measured in the short term. |
| ||||
| Time to next course of antibiotics
| This outcome was not reported in the short term. |
| ||||
| Adverse events during treatment
Follow‐up: 10 ‐ 14 days | There were no differences between single or combination IV antibiotic therapy:
| N/A | 131 | ⊕⊕⊝⊝
| 4 further trials provided narrative information on adverse events. Master reported tinnitus in 2 participants (1 in each group) which was thought to be related to tobramycin (Master 1997). Parry reported phlebitis in 6 participants, eosinophilia in 5 participants and urticaria in 1 participant, all in the single antibiotic group (Parry 1977).
The two remaining trials reported no serious adverse events or incidences of auditory problems or nephrotoxicity in either group (Costantini 1982; Pedersen 1986). | |
| Quality of life
| This outcome was not measured in the short term. |
| ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a. Downgraded once as there was an unclear risk of bias across some domains across the two trials. In one trial the randomisation methods weren't described adequately and both trials had a high dropout rate. b. Downgraded once due to small sample size or low event rate, or both. c. Downgraded once due to risk of bias within one of the included trials, particularly in the domains of sequence generation and blinding. | ||||||
| Single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ long‐term effects | ||||||
| Patient or population: children and adults with cystic fibrosis Settings: inpatient or outpatient Intervention: combination IV antibiotic therapy Comparison: single IV antibiotic | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Single IV antibiotic therapy | Combined IV antibiotic therapy | |||||
| Change in FEV1 (% predicted)
Follow‐up: 6 months
| This outcome was not reported. | 1 trial reported that there was no significant difference in pulmonary function tests, with mean follow‐up time of 20 months; but further commented that sample size restricted statistical power (Master 1997). | ||||
| Change in sputum P aeruginosa density at end of treatment (cfu/g)
| This outcome was not reported in the long term. |
| ||||
| Additional treatment required
| This outcome was not reported in the long term. |
| ||||
| Time to next course of antibiotics
| This outcome was not reported in the long term. |
| ||||
| Adverse events during treatment
Follow‐up: 10 ‐ 14 days | This outcome was not reported in the long term. |
| ||||
| Quality of life Follow‐up: 6 months or more
| 1 trial reported no statistically significant difference in NIH scores between treatment groups at the long‐term follow‐up (mean 20 months for both groups) (Master 1997). |
| ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
Background
Description of the condition
Cystic fibrosis (CF) is the most common life‐limiting inherited disorder affecting populations of Northern European descent (Farrell 2018), with chronic, progressive lung disease being the major cause of morbidity and shortened survival. The continuous cycle of infection and inflammation is responsible for the severe airway damage and loss of respiratory function (Cantin 1995; Gibson 2003).
Recurrent infection, in particular with Pseudomonas aeruginosa, is the main feature of the lung involvement in CF. Antibiotic therapy may be utilised with the aim of preventing, eradicating, or controlling respiratory infections (Castellani 2018; UK CF Trust 2009).
Description of the intervention
Currently, treatment of chronic P aeruginosa infection in people with CF usually involves one of the following strategies. One approach is to use intravenous (IV) antibiotics to treat people with CF only when they become acutely unwell, on the grounds of clinical, radiological or pulmonary function parameters (subsequently referred to as symptomatic regimen). Alternatively, chronic infection may be treated with elective IV antibiotics at regular intervals (e.g. three‐monthly) (Hoiby 1993), with the aim of preventing long‐term deterioration (subsequently referred to as an elective regimen). Trials using either of these strategies will be considered for this review, if the same strategy was used for treatment and comparison groups.
Choice of antibiotic, single or combined therapy and the duration of treatment are contentious areas in the treatment of infection with IV antibiotics in CF. Administration of IV antibiotic therapy for a period of around two weeks is standard practice for treatment of pulmonary infections in most CF centres. Current guidelines acknowledge that this is current practice, but note that evidence is lacking (Castellani 2018; UK CF Trust 2009). Treatment of P aeruginosa is complicated by discordance between antibiotic susceptibility pattern and clinical response (Smith 2003).
How the intervention might work
Most centres perceive dual or combination IV antibiotic therapy in CF to be more effective than single therapy. with the possibility that combination therapy may offer antibiotic synergy (Saiman 1996). It has been suggested that a clinic policy of using monotherapy with a beta‐lactam antibiotic may be responsible for the emergence of resistant strains of P aeruginosa (Cheng 1996). However, the use of a beta‐lactam alone offers advantages for the individual because of ease of administration and the avoidance of aminoglycoside related toxicities (Prayle 2010).
Why it is important to do this review
Intravenous antibiotic therapy may have contributed to improved survival among people with CF; however, the multiple use of potent and highly selective antibiotics may increase the likelihood of adverse effects and lead to the development of resistant strains of organisms (Levy 1998). This version of the review is an update of previous review versions (Elphick 2002; Elphick 2005; Elphick 2014).
Objectives
1. To assess the effectiveness of single compared to combination IV anti‐pseudomonal antibiotic therapy in the treatment of people with CF.
2. To assess whether the use of combination IV anti‐pseudomonal antibiotic therapy leads to an increase in adverse effects or the development of resistant strains of organisms in CF.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs). We included trials using quasi‐randomisation methods such as alternation, if there was sufficient evidence that the treatment and comparison groups were comparable in terms of clinical status at baseline.
Types of participants
Children and adults with defined CF, diagnosed clinically and by sweat or genetic testing, with all degrees of disease severity.
Types of interventions
Trials of any single IV anti‐pseudomonal antibiotic compared to a combination of the same IV anti‐pseudomonal antibiotic plus one or more other IV anti‐pseudomonal antibiotics (drug A versus drug A plus drug B). Trials which compared a single anti‐pseudomonal antibiotic agent with a combination of two further anti‐pseudomonal antibiotics (drug A versus drug B plus drug C) were not included. Symptomatic and elective regimens (see above) were both eligible for inclusion if the only difference between the treatment and comparison group was whether the participants received single or combination antibiotic therapy.
Types of outcome measures
We aimed to assess whether a combination of IV anti‐pseudomonal antibiotics is more effective than a single IV anti‐pseudomonal antibiotic for clinical, bacteriological and subjective changes and in adverse events. Outcomes differed between short‐term results (i.e. at end of course of antibiotics) and long‐term results (measured at 6 to 12 months after course of antibiotics; if long‐term outcomes are measured at other time intervals, we will also consider these).
Short‐term results
Primary outcomes
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Spirometric lung function
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forced expiratory volume in one second (FEV1)
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forced vital capacity (FVC)
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other measures of lung function
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Sputum bacteriology
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eradicaton of P aeruginosa
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bacterial concentration
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antibiotic sensitivity
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Adverse effects to antibiotics, e.g. renal and auditory impairment, serum sickness and sensitivity reactions
Secondary outcomes
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Quality of life (QoL) assessment
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Nutritional status
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change in weight
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change in body mass index (BMI)
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change in z score
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other indices of nutritional status
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Additional treatment required
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Duration of hospitalisation
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Time to next course of IV antibiotics
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Clinical status
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chest X‐ray scores
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other symptom scores, e.g. Schwachman score
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Changes in inflammatory markers (in sputum or blood)
Long‐term results
Primary outcomes
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Change in lung function (prevention of deterioration of lung function)
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Development of antibiotic‐resistant strains of P aeruginosa and other organisms
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Adverse effects to antibiotics, e.g. renal and auditory impairment, serum sickness and sensitivity reactions
Secondary outcomes
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QoL assessment
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Number of courses of IV antibiotics in the following year
Search methods for identification of studies
The authors did not restrict results by language or publication status.
Electronic searches
The authors identified relevant trials from the Group's Cystic Fibrosis Trials Register using the terms: antibiotics AND intravenous.
The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (Clinical Trials) (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 the most recent search of the Group's CF Trials Register: 07 October 2020.
Authors also searched the following online study registries for relevant ongoing trials; please see the appendices for the search strategies (Appendix 1):
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US National Institutes of Health Ongoing Trials Register Clinicaltrials.gov (www.clinicaltrials.gov; 2000 to present);
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World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (apps.who.int/trialsearch; 1994 to present).
Date of latest search: 16 November 2020.
Searching other resources
The authors checked the reference lists of the identified trials for other possibly relevant trials.
Data collection and analysis
Selection of studies
Two review authors independently reviewed all trials to select which were to be included in the review. If disagreement arose on the suitability of a trial for inclusion in the review, the authors reached a consensus by discussion.
Data extraction and management
Each review author independently extracted data using standard data acquisition forms. If disagreement arose on the quality of a trial, the authors reached a consensus by discussion.
If there had been sufficient numbers of trials using quasi‐randomisation methods, then the authors would have analysed this group separately.
The authors grouped data into short‐term results and long‐term results. They defined short‐term results as those at the end of the course of antibiotics (between 10 and 14 days); they considered long‐term results to be six to 12 months after the course of antibiotics. The authors planned to also consider other time intervals if these are reported. In the review the review authors report data at the end of the course of antibiotics (between 10 and 14 days), at two to eight weeks and at 80 days.
For binary outcome measures the authors recorded the number of events and the number of participants for each group. For continuous outcomes, the authors recorded either the mean change from baseline for each group or mean post‐treatment or intervention values and the standard deviation (SD) or standard error (SE) for each group.
Assessment of risk of bias in included studies
In order to establish a risk of bias for each trial, the authors independently assessed the methodological quality of each trial. In particular, authors examined details of the randomisation method (generation and concealment of allocation), the degree of blinding in the trial, whether intention‐to‐treat analyses were possible from the available data and if the investigators recorded the number of participants lost to follow‐up or subsequently excluded from the trial.
Measures of treatment effect
For binary outcome measures, the authors calculated a pooled estimate of the treatment effect for each outcome across trials using the Peto odds ratio (OR) with 95% confidence intervals (CIs) where appropriate. For continuous outcomes, the authors calculated a pooled estimate of treatment effect by calculating the mean difference (MD) with 95% CIs.
Unit of analysis issues
The authors included one cross‐over trial in the review (Pedersen 1986). Ideally when conducting a meta‐analysis combining results from cross‐over trials the authors would have liked to use the inverse variance methods that are recommended by Elbourne (Elbourne 2002). However, due to restrictions on the data that were available from the included trial, the only method that they have been able to use was to treat the cross‐over trial as if it was a parallel trial (assuming a correlation of zero as the most conservative estimate). Elbourne says that this approach produces conservative results as it does not take into account within‐patient correlation (Elbourne 2002). Also each participant appears in both the treatment and control group, so the two groups are not independent.
Dealing with missing data
In order to allow an intention‐to‐treat analysis, the review authors collected data on the number of participants with each outcome event by allocated treatment group, irrespective of compliance and whether or not the participant was later thought to be ineligible or otherwise excluded from treatment or follow‐up. They planned to contact the primary investigators for clarification of data if needed.
Assessment of heterogeneity
Review authors planned to measure the inconsistency of trial results using the Chi² test and the I²heterogeneity statistic to determine if variation in outcomes across trials was due to trial heterogeneity rather than chance (Higgins 2003). This Chi² test assesses whether observed differences in results are compatible with chance alone. A low P value (or a large Chi² statistic relative to its degree of freedom) provides evidence of heterogeneity of intervention effects (variation in effect estimates beyond chance). A P value of 0.10, rather than the conventional level of 0.05, is used to determine statistical significance.
The I²statistic, as defined by Higgins (Higgins 2017), measures heterogeneity as a percentage where a value:
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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.
The importance of the observed value of I² depends on (i) magnitude and direction of effects and (ii) strength of evidence for heterogeneity (e.g. P value from the Chi² test, or a confidence interval for I²).
Assessment of reporting biases
The review authors assessed selective outcome reporting as detailed above (Assessment of risk of bias in included studies). If they had been able to combine at least 10 trials, they would have assessed publication bias by generating a funnel plot (Sterne 2017).
Data synthesis
The review authors analysed the data using a fixed‐effect model. If they had identified at least substantial heterogeneity (as defined above), they would have analysed the data using a random‐effects model.
Subgroup analysis and investigation of heterogeneity
If the review authors had included and combined sufficient trials and identified at least substantial heterogeneity (as defined above), they planned to carry out subgroup analyses of adults separately from children; of participants on a symptomatic regimen separately from those on an elective regimen; and also of those who were colonised with P aeruginosa (i.e. those people with CF who are sputum positive on three consecutive occasions) separately from those who were not colonised.
While the authors were unable to conduct a formal subgroup analysis, they have presented the results of the single trial of elective treatment (reported as median and range) separately in an additional table (Pedersen 1986).
Sensitivity analysis
The review authors planned to perform a sensitivity analysis based on the methodological quality of the trials, removing any trial which had a high risk of bias in any domain.
Summary of findings and assessment of the certainty of the evidence
The authors have prepared a summary of findings table for each comparison presented in the review. They listed each population, setting, intervention and comparison and reported an illustrative risk for the experimental and control intervention. They graded the overall certainty of the body of evidence as high, moderate, low or very low using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) (Schuneman 2006). The authors based their judgements on the risk of bias within the trials, their relevance to the population of interest (indirectness), unexplained heterogeneity or inconsistency, imprecision of the results or high risk of publication bias. They downgraded the evidence once if the risk was serious and twice if the risk was deemed to be very serious and described the rationale for each judgement in footnotes to each table. For each comparison they reported the following outcomes.
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Change in FEV1 % predicted at end of antibiotic course
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Change in FEV1 % predicted at six months
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Change in sputum P aeruginosa density (CFU/g) at end of antibiotic course
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Additional treatment required
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Time to next course of antibiotics
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Adverse events during antibiotic course
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QoL
Results
Description of studies
Please see the tables for additional information (Characteristics of included studies; Characteristics of excluded studies).
Results of the search
The searches identified a total of 59 trials; no trials were found through contact with pharmaceutical companies. The authors included eight trials in the review and excluded 51 trials.
Included studies
Eight trials (including 356 participants) are included in this review; of these two were published only as abstracts in conference proceedings (Costantini 1982; Huang 1982).
Trial design
Seven trials were described as RCTs (Costantini 1982; Huang 1982; Master 1997; McCarty 1988; McLaughlin 1983; Pedersen 1986; Smith 1999). In the remaining trial, treatment was assigned using alternate allocation with good evidence of similar groups at baseline (Parry 1977). This trial was included as a quasi‐RCT.
Seven trials of symptomatic treatment employed a parallel group design (Costantini 1982; Huang 1982; Master 1997; McCarty 1988; McLaughlin 1983; Parry 1977; Smith 1999). The remaining trial of elective treatment every three months used a cross‐over design (Pedersen 1986).
Participants
In seven trials, participants were enrolled during a pulmonary exacerbation (symptomatic regimen) (Costantini 1982; Huang 1982; Master 1997; McCarty 1988; McLaughlin 1983; Parry 1977; Smith 1999). In the remaining trial, participants were treated using a three‐monthly elective regimen and were re‐entered into the trial during consecutive courses of antibiotics in a cross‐over design (Pedersen 1986). In five of the trials, evidence of P aeruginosa in the sputum was an inclusion requirement (Costantini 1982; Master 1997; Parry 1977; Pedersen 1986; Smith 1999); of the remaining three trials, one stated that 98% had P aeruginosa (McLaughlin 1983).
Only one trial stated the criteria for diagnosis of CF (Smith 1999). Sample size varied from 16 participants (Huang 1982) to 83 participants (Master 1997), with a total of 356 participants recruited across all eight trials. All trials either stated that they included both adults and children, or did not state the age range. No trial looked at the effects of single versus combination antibiotic therapy in children alone. One trial included 17 children, but included three children twice, giving a total of 20 treatment courses (McCarty 1988). Similarly, a further two trials reported on participants with multiple admissions a higher number of admissions than participants (Costantini 1982; Master 1997).
Interventions
Treatment duration varied from 10 to 14 days. Three trials included a follow‐up period, which varied from two to eight weeks (McLaughlin 1983; Smith 1999) to six months for the cross‐over trial (Pedersen 1986).
There was a wide variation in the individual antibiotics used in each trial (seePublished notes: Description of pharmacological properties of antibiotics used). Two trials made two comparisons, therefore, in total, the eight trials included seven comparisons of a beta‐lactam antibiotic (penicillin‐related or third generation cephalosporin) to a beta‐lactam‐aminoglycoside combination and three comparisons of an aminoglycoside to a beta‐lactam‐aminoglycoside combination. We did not analyse these two groups of trials separately due to insufficient data.
Two trials compared two single agents with the combination of the same two antibiotics: carbenicillin versus sisomycin versus carbenicillin and sisomycin (Costantini 1982); ticarcillin versus gentamicin versus ticarcillin and gentamicin (Parry 1977). One other trial looked at an aminoglycoside as the single agent: tobramycin versus tobramycin and ceftazidime (Master 1997). Of the remaining five trials, one studied ceftazidime as the single agent (compared to ceftazidime with tobramycin (Pedersen 1986)) and the remaining four compared an agent from the penicillin group of antibiotics: piperacillin (McCarty 1988); ticarcillin (Huang 1982); azlocillin (McLaughlin 1983; Smith 1999) with a combination of that agent with tobramycin.
Outcome measures
Outcomes were studied at the end of the treatment course in all trials.
Five trials reported on lung function: mean FEV1 % predicted and FVC % predicted at the end of the treatment course (McLaughlin 1983; Smith 1999); the mean change from baseline in FEV1 % predicted and FVC % predicted (Master 1997); and median (range) FEV1 % predicted and FVC % predicted at baseline, end of treatment and follow‐up (Pedersen 1986). One trial measured FEV1 and FVC, but did not specify the unit of measurement (McCarty 1988). Two trials undertook a number of other specified lung function measurements (mean RV % predicted, mean TLC % predicted, mean RV/TLC % predicted, mean PFR % predicted and mean MMEF % predicted) (McLaughlin 1983; Smith 1999). Additionally, one trial fed pulmonary function into a clinical scoring system, but did not specify the actual outcome measures or report the pulmonary function results (Huang 1982) and one trial describes performing pulmonary function tests when possible, but does not define what these were (Parry 1977).
Three trials reported on Schwachman score (McCarty 1988; McLaughlin 1983; Parry 1977); one trial reported exacerbation scores (Smith 1999); one trial reported a combination clinical score (Costantini 1982) and a further trial devised their own composite clinical score (Huang 1982).
Three trials reported on eradication of P aeruginosa (Costantini 1982; Huang 1982; Pedersen 1986), two trials reported on the change in P aeruginosa density (McCarty 1988; Smith 1999) and one trial reported on a change in sputum bacterial concentration (McLaughlin 1983). Six trials reported adverse events (Costantini 1982; Master 1997; McCarty 1988; Parry 1977; Pedersen 1986; Smith 1999).
Two trials reported of nutrition (Parry 1977; McCarty 1988). Two trials reported on hospitalisations (Huang 1982; Smith 1999) and two trials on the time to next course of antibiotics (McLaughlin 1983; Parry 1977). Three trials reported short‐term changes in chest X‐ray scores (Costantini 1982; Huang 1982; Parry 1977). One trial reported sputum markers of inflammation (Smith 1999) and three trials reported blood markers of inflammation (Parry 1977; Pedersen 1986; Smith 1999). Six of the eight trials examined sputum for drug sensitivity at the beginning and at the end of treatment (Costantini 1982; Huang 1982McCarty 1988; McLaughlin 1983; Parry 1977; Pedersen 1986; Smith 1999).
One trial included longer‐term results and reported no difference in pulmonary function tests or NIH scores (Master 1997).
Excluded studies
A total of 51 trials were excluded. In 11 trials a single antibiotic agent was compared with a combination of two other antibiotics (drug A versus drug B plus drug C) (Balsamo 1986; Beaudry 1980; Bosso 1988; Church 1997; De Boeck 1989; De Boeck 1999; Gold 1985; Jewett 1985; Permin 1983; Stack 1985; Wesley 1988). Different dosage regimens of the same antibiotic were compared in 16 trials (Adeboyeku 2011; Al‐Ansari 2006; Aminimanizani 2002; Beringer 2012; Conway 1997; Hubert 2009; Keel 2011; McCabe 2013; Prayle 2016; Noah 2010; NCT01667094; NCT01694069; Riethmueller 2009; Semykin 2010; Turner 2013; Whitehead 2002). Two trials compared different durations of IV antibiotics (NCT01044719; STOP 2 2018). Three trials were excluded as they compared two single drugs (Al‐Aloul 2004; Levy 1982; NCT02918409 ). One trial compared two IV antibiotics to those same antibiotics plus an inhaled antibiotic (Al‐Aloul 2019) and one trial compared a single IV antibiotic to a combination of IV and inhaled antibiotics (NCT03066453). A further trial had a similar design but the third antibiotic in the comparator group was identified through examination of the microbiome and it was not specified how this third antibiotic was administered (CFMATTERS 2017). Similarly, one trial compared IV antibiotic treatment identified by standard testing to treatment identified from biofilm susceptibility testing (Moskowitz 2011). One trial compared an IV regimen to control (Enaud 2017) and one trial as investigators compared two different combinations of antibiotics (Blumer 2005). One trial compared IV antibiotics administered in hospital compared to at home (Donati 1987) and two trials looked at an eradication regimen (Kenny 2009; TORPEDO 2018). One trial compared oral antibiotics to IV antibiotics (Park 2018). Six further trials were excluded as allocation was not by randomisation and because there were marked differences in baseline characteristics between the treatment and comparison groups (Hoogkamp 1983; Hyatt 1981; Krause 1979; Nelson 1985; NCT02421120; Roberts 1993). Two trials were excluded as they evaluated tools to assess treatment response (Hatziagorou 2013; Kuni 1992).
One trial included 30 participants. However, 17 of these received more than one course of treatment (Padoan 1987). In total, 40 courses of treatment took place (20 in each intervention group). The trial was cross‐over in design; but re‐randomisation took place between courses of treatment, resulting in some participants possibly receiving two or more courses of the same treatment, or a mixture of different treatments. Since the number of participants receiving each treatment was unclear, results could not be included in the analysis of this review and therefore the trial was excluded. Individual patient data are being requested from the authors of this trial so that data from this trial may be included in future updates (Padoan 1987).
Risk of bias in included studies
In earlier versions of the review, in order to assess the risk of bias in the trials, the review authors assessed the methodological quality of each trial using the following criteria: generation of allocation sequences; concealment of allocation schedule; inclusion in the analysis of all randomised participants; and double‐blinding (Schulz 1995).
For the current version of the review the review authors have used the Cochrane risk of bias tool judging the trials to have a low, unclear or high risk of bias (Higgins 2017).
Allocation
Generation of sequence
The authors assessed two trials as having a low risk of bias; one trial stated that participants were allocated to treatment groups using computer‐generated randomisation (Smith 1999) and one trial was stratified for age and disease severity during randomisation (Master 1997). Five trials had an unclear risk of bias as they stated that allocation was randomised, but did not specify the method of sequence generation (Costantini 1982; Huang 1982; McCarty 1988; McLaughlin 1983; Pedersen 1986). One trial used alternation but does not discuss how the first participant was randomised to their treatment group and the authors assessed this as inadequate, thus having a high risk of bias (Parry 1977).
Allocation concealment
The authors assessed four trials as adequately concealing the allocation schedule leading to a low risk of bias (Master 1997; McCarty 1988; McLaughlin 1983; Smith 1999). Master stated that the code was only broken on completion of the study (Master 1997); another trial stated they used sequentially numbered envelopes (McCarty 1988); a further trial employed sealed envelopes prepared by pharmacy (McLaughlin 1983); and the fourth trial stated central randomisation (Smith 1999). The review authors assessed one trial as inadequately concealing the allocation schedule, since the investigators used alternate allocation, and judged this trial to have a high risk of bias (Parry 1977). In the remaining three trials the method of allocation concealment was unclear and so the reveiw authors judged these to have an unclear risk of bias (Costantini 1982; Huang 1982; Pedersen 1986).
Blinding
Five of the trials were described as double‐blinded as they used saline for the placebo injection (Huang 1982; Master 1997; McLaughlin 1983; Smith 1999). The review authors judged these trials to have a low risk of bias. One trial did not explicitly state that blinding had taken place, but did state that both interventions were given with the same volume and in the same way, so the review authors assumed that there was some degree of blinding leading to a low risk of bias (Pedersen 1986). Two further trials stated that no blinding had taken place, thus the review authors deemed these to have a potential risk of bias (McCarty 1988; Parry 1977); and in the remaining trial it was not clear whether blinding had taken place and the review authors judged this to have an unclear risk of bias (Costantini 1982).
Incomplete outcome data
An intention‐to‐treat analysis was not stated in any of the included trials. In four, however, there appeared to be no withdrawals and so a low risk of attrition bias (Costantini 1982; Huang 1982; McCarty 1988; Parry 1977). Three trials described numbers of withdrawals and reasons for these, so the review authors judged these to also have a low risk of bias (Master 1997; Pedersen 1986; Smith 1999). Master published a flow chart showing numbers randomized and included or excluded (with reasons) at each stage in paper (Master 1997). Pedersen described reasons why three participants out of a cohort of 20 withdrew (Pedersen 1986). Smith stated that 35 out of 111 participants withdrew (21 from one group) and presented the reasons for withdrawals in a table (Smith 1999).
In the remaining trial, seven of the 41 participants did not complete the trial, six from the single therapy group and one from the combination group (reasons given); the review authors judged this trial to have an unclear risk of bias as although 17% of participants withdrew and nearly all were from one group, the reasons do not indicate an overall direct negative or positive relationship with the intervention (McLaughlin 1983).
Selective reporting
In three trials the outcomes stated in the methods section were reported in the results section of the trial reports, so the review authors judged these to have a low risk of reporting bias (Master 1997; McLaughlin 1983; Pedersen 1986). They judged four trials to have an unclear risk of bias (Costantini 1982; Huang 1982; McCarty 1988; Smith 1999). Two trials were reported as abstracts only and since the protocols were not available and we were not able to compare the methods sections to the results sections in full reports (Costantini 1982; Huang 1982); and in two trials some clinical outcomes specified in the methods not directly reported and only summarised with brief narrative (McCarty 1988; Smith 1999). In the final trial, investigators state that "pulmonary function tests were performed when possible", but no further details or results are given, the review authors therefore judged this trial to have a high risk of bias (Parry 1977).
Other potential sources of bias
Two trials were reported as abstracts only and the review authors were unable to identify any other potential sources of bias and have judged these to have an unclear risk for this domain (Costantini 1982; Huang 1982). One trial undertook a power calculation to show an absolute difference in FEV1 % predicted of 2%, but the sample size was not achieved, therefore the review authors judged this to have an unclear risk of bias (Master 1997).
The remaining five trials had a low risk of bias, these were published as full papers and the review authors did not identify any other potential sources of bias (McCarty 1988; McLaughlin 1983; Parry 1977; Pedersen 1986; Smith 1999).
Effects of interventions
See: Summary of findings 1 Summary of findings: single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ short‐term effects; Summary of findings 2 Summary of findings: Single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ long‐term effects
Only those primary and secondary outcomes of this review, which were reported within the eight included trials, are listed below. Only one trial included results of follow‐up at over six months (Master 1997).
Single compared to combination therapy
Pooling of results was difficult because of missing data, differences in the methods of expression of the results and missing SDs. In this comparison the authors present eight trials with 356 participants (Costantini 1982; Huang 1982; Master 1997; McCarty 1988; McLaughlin 1983; Parry 1977; Pedersen 1986; Smith 1999).
Short‐term results
Primary outcomes
1. Change in spirometric lung function
Although the outcome measure given in our protocol was improvement in spirometric lung function (now described as 'change' rather than improvement), no trial included these data.
Seven of the eight trials included lung function in some form as an outcome measure. However, there was great variety between the trials in the tests used, the time at measurement and the method of expression of the results. One trial, reported as an abstract only, fed pulmonary function into a clinical scoring system, but did not specify the actual outcome measures or report the pulmonary function results (Huang 1982). One trial states that "pulmonary function tests were performed when possible", but no further details or results are given (Parry 1977).
a. FEV1
Two trials measured mean FEV1 % predicted at the end of the treatment course (McLaughlin 1983; Smith 1999). These trials were randomised and gave baseline data, clearly stating that there was no significant difference between the single and combination treatment groups at baseline. We therefore analysed these outcomes and found no difference in FEV1 % predicted between single or combination therapy at 10 to 14 days (two trials, 93 participants; low‐certainty evidence) or at two to eight weeks (one trial, 41 participants) (Analysis 1.1).
One trial reported the mean absolute change in FEV1 % predicted from baseline to 10 days, but the data were based on 44 participants with 98 admissions so we are unable to analyse these in RevMan (Master 1997). However, investigators state that the mean (SD) change with combination antibiotics of 12.8% (13.5) compared to 10.6% (8.5) with a single antibiotic was statistically significant (P < 0.05). By the end of the study (a minimum of 12 months) the median (range) change in FEV1 % predicted was ‐2.2 (‐19.3 to 8.4) in the combination group compared to ‐5.8 (‐22.0 to 3.0) in the single antibiotic group (Master 1997)
The elective trial expressed the results for FEV1 % predicted in terms of a median and range at baseline, end of treatment and after 90 days (Pedersen 1986). Full details are presented in the additional tables (Table 1).
| Time point | Outcome | Combination antibiotics | Single antibiotic |
|---|---|---|---|
| Day 1 | FEV1 % predicted | 56 (35 to 74) | 53 (33 to 68) |
| FVC % predicted | 57 (39 to 79) | 54 (38 to 67) | |
| Day 14 | FEV1 % predicted | 69 (56 to 83) | 66 (52 to 81) |
| FVC % predicted | 72 (60 to 85) | 64 (53 to 83) | |
| Day 90 | FEV1 % predicted | 53 (27 to 70) | 55 (33 to 75) |
| FVC % predicted | 67 (33 to 76) | 59 (45 to 80) |
FEV1: forced expiratory volume at 1 second
FVC: forced vital capacity
One trial reported "similar improvement" in FEV1 but did not give any further details (McCarty 1988).
b. FVC
Two trials measured mean FVC % predicted at the end of the treatment course (McLaughlin 1983; Smith 1999). These trials were randomised and gave baseline data, clearly stating that there was no significant difference between the single and combination treatment groups at baseline. We therefore analysed these outcomes and found no difference in FVC % predicted between the two treatment groups at at 10 to 14 days (two trials, 93 participants) or at two to eight weeks (one trial, 41 participants) (Analysis 1.2).
The Master trial reported the mean absolute change in FVC % predicted from baseline to 10 days, but the data were based on 44 participants with 98 admissions so we are unable to analyse these in RevMan (Master 1997). However, investigators state that FVC % predicted the mean (SD) change from baseline was significantly greater (P < 0.05) in the combination group, 12.1% (12.0), compared to 9.9% (9.1) in the single antibiotic group (Master 1997).
The elective trial expressed the results for FVC % predicted in terms of a median and range at baseline, end of treatment and after 90 days (Pedersen 1986). Full details are presented in the additional tables (Table 1).
McCarty also reported "similar improvement" in FVC, but did not give any further details (McCarty 1988).
c. Other measures of lung function
Two trials reported a range of other measures of lung function, but found no differences between single or combination antibiotic treatments: mean RV % predicted (Analysis 1.3); mean TLC % predicted (Analysis 1.4); mean RV/TLC % predicted (Analysis 1.5); mean PFR % predicted (Analysis 1.6); and mean MMEF % predicted (Analysis 1.7).
2. Sputum bacteriology
a. Eradication of P aeruginosa
Three trials reported on eradication of P aeruginosa (Costantini 1982; Huang 1982, Pedersen 1986). At up to 14 days, Huang found no difference between the single or combination antibiotic groups, but at two to eight weeks Costantini reported more cases of eradication in the single antibiotic group than the combination group, OR 10.16 (95% CI 1.44 to 71.65) (Analysis 1.8). The elective trial stated that neither treatment succeeded in eradication P aeruginosa from participants (Pedersen 1986).
b. Bacterial concentration
One trial reported the change in sputum P aeruginosa density in colony forming units per gram (cfu/g) (Smith 1999). This trial showed a significant decrease in P aeruginosa density in both treatment groups at the end of treatment, with a greater decrease in the combination group. The difference between groups in the mean change in density was MD ‐1.60 (95% confidence interval (CI) ‐9.51 to 6.31) (Analysis 1.9), i.e. the mean decrease in P aeruginosa density was 1.6 cfu/g greater in the combination treatment group than for the single treatment group (moderate‐certainty evidence). However, on follow‐up, the density of P aeruginosa in the sputum was similar in both groups.
One trial reported a change in sputum bacterial concentration in mean log cfu/mL, with a significant reduction in concentration of bacteria between days 1 and 10 in both combination treatment groups (P ≤ 0.01) and a non‐significant reduction in the single treatment group (P value not given) (McLaughlin 1983). At three‐month follow‐up, the investigators state that bacterial concentration returned to a similar level as pre‐treatment. Although this data is demonstrated in a figure, the numerical values are not included in the text (McLaughlin 1983).
One trial reported 19 P aeruginosa isolates from each group; however, since only 17 participants were randomised in the trial the data are not independent and can not be analysed in RevMan (McCarty 1988). Investigators reported that only 5 out of 19 isolates in the single antibiotic (piperacillin) group decreased in titer by greater than 10² cfu/mL compared to 12 out of 19 isolates in the combination (piperacillin plus tobramycin) group (McCarty 1988).
One trial was not able to compare sputum density on days 1 and 10 as most participants were unable to expectorate on day 10 (Master 1997).
c. Antibiotic sensitivity
Six of the eight trials examined sputum for drug sensitivity at the beginning of the trial; five of these defined sensitivity in terms of minimum inhibitory concentration (MIC). One trial found that the disc diffusion method did not identify resistant strains (Smith 1999). The trials varied in their definitions of resistance, e.g. resistance to tobramycin was defined as MIC greater than 8 μg/ml in one trial (McLaughlin 1983) and as MIC greater than 32 μg/ml in another (Master 1997). No trial used antibiotic sensitivity in their entry criteria. In one trial, the bacteria were clearly sensitive to the antibiotics used (Pedersen 1986). This trial gave mean MIC values at baseline and the end of the treatment course and found no significant change. Parry reported MIC values for all the isolates for ticarcillin and carbenicillin and found that the median MIC value for ticarcillin at two to six months post‐treatment was same as the pre‐treatment value (3.1 μg/mL), but investigators did not define antibiotic resistance (Parry 1977). One further trial stated that there was no significant difference between the single and combination groups at the beginning of the treatment period, and that emergence of resistance was not seen with any isolate (McCarty 1988). The remaining trial states that sputum cultures were tested for antibiotic sensitivity but gives no further information (Costantini 1982).
In the two trials included in the analysis, the number of participants developing resistant strains of P aeruginosa at baseline, end of treatment and follow‐up at between two and eight weeks was reported (McLaughlin 1983; Smith 1999). For completeness, we have shown each of these analyses on the forest plot, as well as the difference between baseline and follow‐up in two of the trials. The second trial could not be represented in the latter analysis, as the total numbers of participants changed from baseline to follow‐up (Smith 1999). McLaughlin classified bacteria as resistant to tobramycin if the MIC was greater than 8 μg/ml and to azlocillin if the MIC was greater than 125 μg/ml (McLaughlin 1983). Smith defined resistance to tobramycin if the MIC was greater than 8 μg/ml and for azlocillin, if the MIC was greater than 100 μg/ml (Smith 1999).
The result of the analysis showed that the difference between the single and combination therapy groups was not significant at baseline or at the end of the treatment course (Analysis 1.10). At two to eight weeks follow‐up, both trials individually showed an increase in the number of participants with resistant strains of P aeruginosa with single therapy, but the aggregated results showed that the difference was not significant. However, the aggregation of the studies at follow‐up included a relatively small number of participants, with a total of 40 participants in each group. Calculation of the difference between the numbers of participants with resistant strains from baseline to two to eight weeks post‐treatment also favoured combination treatment, although the difference was not significant.
3. Adverse events
Two trials reported analysable data for adverse events (McCarty 1988; Smith 1999). The most commonly reported were: local erythema at the injection site; generalised rash; fever; renal impairment and proteinuria; auditory impairment; and hypersensitivity reaction, with no differences found between treatment groups (Analysis 1.11).
The only adverse event in the Master trial was tinnitus, which was experienced by one participant in each group and was thought to be related to inadvertent rapid administration of tobramycin (Master 1997). The three‐arm Parry trial reported adverse events which were probably drug‐related for each of the single antibiotic arms (Parry 1977). In the ticarcillin arm (n = 28) phlebitis was reported by six participants, eosinophilia by five participants and urticaria by one participant; in the gentamicin arm cylinduria was reported by one participant (Parry 1977). Costantini reported there were no incidences of either auditory or nephrotoxicity (Costantini 1982).
The elective trial reported that no serious adverse events were recorded during either treatment arm (Pedersen 1986).
Secondary outcomes
2. Nutritional status
a. Change in weight
Two trials report that weight gain was similar between the two treatment groups (McCarty 1988; Parry 1977).
4. Hospitalisation
Two trials measured the number of participants readmitted to hospital within given time periods of one month (Huang 1982) and 80 days (Smith 1999). Huang found no significant difference between the two groups (Huang 1982). The results from the Smith trial favoured combination therapy, Peto OR 0.30 (95% CI 0.12 to 0.73) (Smith 1999) (Analysis 1.12).
A further trial reported on the mean number of weeks that participants remained out of hospital within the three month follow‐up period (McLaughlin 1983). There was no difference found between the single or combination groups (Analysis 1.13).
5. Time to next course of antibiotics
Only one trial reported the effect on the time to next course of antibiotics (McLaughlin 1983). There was no significant difference between the two groups (Analysis 1.13). A futher trial reported that time interval to next course of antibiotics did not differ significantly between treatment groups but no numerical data was provided (Parry 1977).
6. Clinical status
a. Chest x‐ray scores
One trial reports that chest x‐rays (assessed with Chrispin‐Norman scores) only showed significant improvement in the antibiotic combination group but no numerical data was provided (Costantini 1982). One trial reported no difference between treatment groups of "percentage improvement in chest radiograph" without information regarding how this percentage was calculated (Parry 1977). One trial devised their own scoring system consisting of a combination of clinical, radiological and pulmonary function factors and reported no difference between group scores either before or after treatment (Huang 1982).
b. Other symptom scores
One trial measured mean Schwachman score (McLaughlin 1983); groups did not significantly differ at baseline and analysis of the data found no difference between groups at the end of treatment (Analysis 1.14). A second trial reporting Schwachman score described similar improvements in both groups (McCarty 1988). A further three‐arm trial presented baseline Schwachmann scores in a table, but the paper does not report post‐treatment values (Parry 1977).
One trial reported that the exacerbation score decreased significantly (P < 0.001) in each group and remained lower than the admission values at the follow‐up assessment (Smith 1999). One trial devised their own scoring system consisting of a combination of clinical, radiological and pulmonary function factors and reported no difference between group scores either before or after treatment (Huang 1982). One trial reported that "clinical improvement was obtained in the 80% ‐ 90% of patients regardless of the therapeutic regimen" according to a clinical score that included serological and clinical factors (Costantini 1982).
7. Changes in inflammatory markers
One trial reported blood or sputum markers of inflammation (Smith 1999). This trial reported mean white blood cell (WBC) count at the end of the antibiotic course and involved treatment groups with similar baseline characteristics. There was no significant difference between the groups (Analysis 1.15). One trial reported no difference in change of white blood cell count or sedimentation rate between treatment groups (Parry 1977). One trial reported a statistically significant decrease in white blood cell count in both treatment groups, with no difference between groups (Pedersen 1986).
Long‐term results
Primary outcomes
1. Change in lung function
One trial reported that there was no significant difference in pulmonary function tests, with mean follow‐up time of 20 months; but further commented that sample size restricted statistical power (Master 1997).
Secondary outcomes
1. QoL
One trial reported no statistically significant difference in NIH scores between treatment groups (Master 1997).
Discussion
Choice of anti‐pseudomonal antibiotic and the use of single or combined therapy are controversial areas in the treatment of respiratory infection in CF. Current practice is variable. Advantages of combination therapy include a wider range of modes of action, possible synergy and reduction of resistant organisms; whereas advantages of monotherapy include lower cost and a reduction of drug‐related toxicity. From the perspective of people with CF, using a beta‐lactam alone offers such advantages as ease of administration and no requirement for blood sampling to measure aminoglycoside levels. Current evidence does not provide a clear answer and, therefore, the use of IV antibiotic therapy in CF requires further evaluation.
Summary of main results
This review has found eight trials that examined the effect of single compared to combination IV anti‐pseudomonal antibiotic therapy, seven of these were for acute exacerbations in CF (Costantini 1982; Huang 1982; Master 1997; McCarty 1988; McLaughlin 1983; Parry 1977; Smith 1999) and one examined an elective quarterly regimen (Pedersen 1986). There was considerable heterogeneity amongst these trials, which led to difficulties in performing the review and interpreting the results. We were unable to perform adequate meta‐analysis for most outcome measures.
Short‐term results
While most included trials reported on lung function, there was great variety in the tests used, the time points reported and how the results were reported. The overall results from our limited analysis (two trials, 93 participants; low‐certainty evidence) showed that there was no difference between monotherapy and combination therapy (either symptomatic or elective regimen) in terms of lung function at the end of treatment for an exacerbation (McLaughlin 1983; Smith 1999). Other trials also reported similar narrative results for lung function for single and combination treatment regimens; although one symptomatic trial presented data for participants with multiple admissions and reported a greater increase in both FEV1 % predicted and FVC % predicted with combination antibiotics compared to a single antibiotic (Master 1997). In the elective trial, the median (range) values for lung function (FEV1 and FVC % predicted) demonstrated similar increases from baseline to 14 days which then returned to baseline levels at 90 days (Pedersen 1986).
At up to 14 days, one study (n = 25) found no difference in P aeruginosa eradication between the single or combination antibiotic groups (Huang 1982), but at two to eight weeks a further trial (n = 18) reported more cases of eradication in the single antibiotic group than the combination group (Costantini 1982). The elective trial stated that neither treatment succeeded in eradication P aeruginosa from participants (Pedersen 1986). There were no further differences in terms of bacteriological outcomes.
Five symptomatic trials and the elective trial reported adverse effects of treatment (data were available from three symptomatic trials (Master 1997; McCarty 1988; Smith 1999)), but no differences between single or combination antibiotics were identified. Two trials reported similar weight gain in both treatment groups (McCarty 1988; Parry 1977). Two trials reported on hospitalisations (Huang 1982; Smith 1999), but only one found a difference between groups (favouring combination therapy) (Smith 1999); two trials reporting the time to the next course of antibiotics found no difference between groups (McLaughlin 1983; Parry 1977). No trial reporting symptom scores found any difference between single or combination antibiotics, e.g. Schwachman scores (McCarty 1988; McLaughlin 1983), an exacerbation score (Smith 1999) and a trial‐specific clinical score (Huang 1982). We found no effect on inflammatory markers or on resistant strains of P aeruginosa.
Long‐term results
Only one trial (n = 51) reported limited long‐term results (at 20 months) (Master 1997). Investigators found no difference between symptomatic single or combination antibiotic treatment in pulmonary function tests or QoL (NIH scores); but further commented that sample size restricted statistical power (Master 1997). The trial did not report any other outcomes of this review.
Overall completeness and applicability of evidence
The trials were very heterogeneous in terms of design, drugs used, duration of treatment and follow‐up and outcome measures. Inconsistencies in expression of results and statistical reporting made meta‐analysis impossible in most cases and individual patient data would need to be collected from authors to clarify these issues. It was disappointing that only four trials included data that were possible to analyse. Most of the outcome measures analysed included data from only one or two trials. Due to the small number of trials, it was not possible to examine for effects of trial quality, type of antibiotic or treatment regimen using sensitivity and subgroup analyses.
In our protocol we stated that we would like to compare the differences between adults and children. This was not possible, as no trial looked at children alone. No trial looked specifically at QoL scores. While there were some short‐term data on resistant strains of P aeruginosa and side effects, there were no data for these outcomes in the long term. This may be relevant particularly to children, in whom there is emerging evidence of ototoxicity due to chronic use of aminoglycosides (Katbamna 1998; Mulherin 1991). Only six of the eight trials stated that they had looked for adverse effects (Costantini 1982; Master 1997; McCarty 1988; Parry 1977; Pedersen 1986; Smith 1999); therefore there may have been side effects that have not been identified. The longest follow‐up in all but one trial in this systematic review was six months, but the majority of trials did not have any follow‐up after the acute course of antibiotics. Potential problems with development of drug‐resistant bacteria, which may shorten long‐term survival, may not be detected in trials of such short duration covered by this review.
Quality of the evidence
These results should be interpreted with caution. All but two of the included trials were published between 1977 and 1988; these were single‐centre trials with flaws in the randomisation process. Furthermore, the sample sizes were too small to have the power to detect a difference between the two groups. Three of the eight trials were not published as full papers. Overall, the methodological quality was poor: only one trial was considered to have adequate randomisation allocation and concealment (Smith 1999); only four were double‐blinded; and none stated any intention‐to‐treat analysis. Using the GRADE framework, we downgraded the certainty of evidence for short‐term effects due to risk of bias issues and small sample sizes (summary of findings Table 1). There was insufficient information and data for us to carry out GRADE assessments for the long‐term trials (summary of findings Table 2).
The review raises some interesting methodological issues, including the difficulties of pooling results from a number of small trials that are of poor quality.
Potential biases in the review process
Comprehensive searches were undertaken and the review authors are confident that all eligible trials have been identified. For each iteration of the review, two authors have independently assessed studies and the data presented in this review, in order to minimise any potential biases or errors.
Agreements and disagreements with other studies or reviews
A review of current evidence was performed by a committee established by the Cystic Fibrosis Foundation, who agree that there is insufficient evidence to support use of either single or combination therapy; however, they recognise that standard practice is to treat with combination therapy and do not feel there is sufficient evidence to recommend changing this strategy (Flume 2008).
This version of the review is an update of previous review versions (Elphick 2002; Elphick 2005; Elphick 2014).
Comparison 1: Single versus combination antibiotics, Outcome 1: FEV1 % predicted (mean absolute values at end of course)
Comparison 1: Single versus combination antibiotics, Outcome 2: Mean FVC at end of course (% pred)
Comparison 1: Single versus combination antibiotics, Outcome 3: Mean RV at end of course (% pred)
Comparison 1: Single versus combination antibiotics, Outcome 4: Mean TLC at end of course (% pred)
Comparison 1: Single versus combination antibiotics, Outcome 5: Mean RV/TLC at end of course (% pred)
Comparison 1: Single versus combination antibiotics, Outcome 6: Mean PFR at end of course (% pred)
Comparison 1: Single versus combination antibiotics, Outcome 7: Mean MMEF at end of course (% pred)
Comparison 1: Single versus combination antibiotics, Outcome 8: Number of Pseudomonas isolates eradicated at end of course
Comparison 1: Single versus combination antibiotics, Outcome 9: Mean change Pseudomonas density in cfu/g at end of course
Comparison 1: Single versus combination antibiotics, Outcome 10: Number resistant strains of Pseudomonas aeruginosa
Comparison 1: Single versus combination antibiotics, Outcome 11: Number adverse events
Comparison 1: Single versus combination antibiotics, Outcome 12: Number readmitted to hospital
Comparison 1: Single versus combination antibiotics, Outcome 13: Mean time to next course of antibiotics (weeks)
Comparison 1: Single versus combination antibiotics, Outcome 14: Mean Schwachman score at end of course
Comparison 1: Single versus combination antibiotics, Outcome 15: Mean WBC count at end of course
| Single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ short‐term effects | ||||||
| Patient or population: children and adults with cystic fibrosis Settings: inpatient or outpatient Intervention: combination IV antibiotic therapy Comparison: single IV antibiotic | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Single IV antibiotic therapy | Combined IV antibiotic therapy | |||||
| Change in FEV1 % predicted at end of antibiotic course: absolute post‐treatment values
Follow‐up: 10 ‐ 14 days | The mean FEV1 (% predicted) ranged across control groups from | The mean FEV1 (% predicted) in the intervention groups was | MD 5.25 (95% CI ‐9.14 to 19.64) | 93 | ⊕⊕⊝⊝
| 3 further trials reported on this outcome, but it was not possible to include the data in our analyses. Master reported that the combination antibiotic group had a significantly higher FEV1 % predicted after 10 days of treatment (P < 0.05) (Master 1997). McCarty reported a "similar improvement" in FEV1 in both groups but no further detail (McCarty 1988). The elective trial reported higher median values for FEV1 % predicted in the combination group at baseline and Day 14, but at Day 90 the median was higher in the single antibiotic group (Pedersen 1986). |
| Change in sputum P aeruginosa density at end of treatment (cfu/g)
Follow‐up: 10 ‐ 14 days | The mean (SD) sputum P aeruginosa density was 6.9 cfu/g (15.5) in the control group. | The mean sputum P aeruginosa density in the intervention groups was | MD ‐1.60 cfu/g (95% CI ‐9.51 to 6.31) | 76 | ⊕⊕⊕⊝
| 2 further trials looked at bacterial concentration, but used different measures and reported within‐group differences only. McLaughlin reported a significant decrease in bacterial concentration (cfu/mL) in the combination group and a non‐significant decrease in the single antibiotic group (McLaughlin 1983). McCarty reported 5/19 P aeruginosa isolates in the single therapy group decreased in titre by more than 10² cfu/mL compared to 12/19 P aeruginosa isolates in the combination group (McCarty 1988). |
| Additional treatment required
| This outcome was not measured in the short term. |
| ||||
| Time to next course of antibiotics
| This outcome was not reported in the short term. |
| ||||
| Adverse events during treatment
Follow‐up: 10 ‐ 14 days | There were no differences between single or combination IV antibiotic therapy:
| N/A | 131 | ⊕⊕⊝⊝
| 4 further trials provided narrative information on adverse events. Master reported tinnitus in 2 participants (1 in each group) which was thought to be related to tobramycin (Master 1997). Parry reported phlebitis in 6 participants, eosinophilia in 5 participants and urticaria in 1 participant, all in the single antibiotic group (Parry 1977).
The two remaining trials reported no serious adverse events or incidences of auditory problems or nephrotoxicity in either group (Costantini 1982; Pedersen 1986). | |
| Quality of life
| This outcome was not measured in the short term. |
| ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a. Downgraded once as there was an unclear risk of bias across some domains across the two trials. In one trial the randomisation methods weren't described adequately and both trials had a high dropout rate. b. Downgraded once due to small sample size or low event rate, or both. c. Downgraded once due to risk of bias within one of the included trials, particularly in the domains of sequence generation and blinding. | ||||||
| Single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ long‐term effects | ||||||
| Patient or population: children and adults with cystic fibrosis Settings: inpatient or outpatient Intervention: combination IV antibiotic therapy Comparison: single IV antibiotic | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Single IV antibiotic therapy | Combined IV antibiotic therapy | |||||
| Change in FEV1 (% predicted)
Follow‐up: 6 months
| This outcome was not reported. | 1 trial reported that there was no significant difference in pulmonary function tests, with mean follow‐up time of 20 months; but further commented that sample size restricted statistical power (Master 1997). | ||||
| Change in sputum P aeruginosa density at end of treatment (cfu/g)
| This outcome was not reported in the long term. |
| ||||
| Additional treatment required
| This outcome was not reported in the long term. |
| ||||
| Time to next course of antibiotics
| This outcome was not reported in the long term. |
| ||||
| Adverse events during treatment
Follow‐up: 10 ‐ 14 days | This outcome was not reported in the long term. |
| ||||
| Quality of life Follow‐up: 6 months or more
| 1 trial reported no statistically significant difference in NIH scores between treatment groups at the long‐term follow‐up (mean 20 months for both groups) (Master 1997). |
| ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Time point | Outcome | Combination antibiotics | Single antibiotic |
|---|---|---|---|
| Day 1 | FEV1 % predicted | 56 (35 to 74) | 53 (33 to 68) |
| FVC % predicted | 57 (39 to 79) | 54 (38 to 67) | |
| Day 14 | FEV1 % predicted | 69 (56 to 83) | 66 (52 to 81) |
| FVC % predicted | 72 (60 to 85) | 64 (53 to 83) | |
| Day 90 | FEV1 % predicted | 53 (27 to 70) | 55 (33 to 75) |
| FVC % predicted | 67 (33 to 76) | 59 (45 to 80) | |
| FEV1: forced expiratory volume at 1 second | |||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 FEV1 % predicted (mean absolute values at end of course) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 at 10 to 14 days | 2 | 93 | Mean Difference (IV, Fixed, 95% CI) | 5.25 [‐9.14, 19.64] |
| 1.1.2 at 2 to 8 weeks | 1 | 41 | Mean Difference (IV, Fixed, 95% CI) | 0.50 [‐57.36, 58.36] |
| 1.2 Mean FVC at end of course (% pred) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 at 10 to 14 days | 2 | 93 | Mean Difference (IV, Fixed, 95% CI) | 1.84 [‐11.44, 15.12] |
| 1.2.2 at 2 to 8 weeks | 1 | 41 | Mean Difference (IV, Fixed, 95% CI) | 6.90 [‐50.50, 64.30] |
| 1.3 Mean RV at end of course (% pred) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.3.1 at 10 to 14 days | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.4 Mean TLC at end of course (% pred) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.4.1 at 10 to 14 days | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.5 Mean RV/TLC at end of course (% pred) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.5.1 at 10 to 14 days | 1 | 64 | Mean Difference (IV, Fixed, 95% CI) | ‐1.40 [‐40.68, 37.88] |
| 1.5.2 At 2 to 8 weeks | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | ‐5.20 [‐54.27, 43.87] |
| 1.6 Mean PFR at end of course (% pred) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.6.1 at 10 to 14 days | 2 | 91 | Mean Difference (IV, Fixed, 95% CI) | 3.21 [‐11.49, 17.91] |
| 1.6.2 At 2 to 8 weeks | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | 2.30 [‐60.90, 65.50] |
| 1.7 Mean MMEF at end of course (% pred) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.7.1 at 10 to 14 days | 2 | 91 | Mean Difference (IV, Fixed, 95% CI) | 7.17 [‐8.22, 22.55] |
| 1.7.2 At 2 to 8 weeks | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | ‐1.90 [‐73.27, 69.47] |
| 1.8 Number of Pseudomonas isolates eradicated at end of course Show forest plot | 2 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.8.1 at 10 to 14 days | 1 | 16 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 6.34 [0.51, 78.02] |
| 1.8.2 2 to 8 weeks | 1 | 18 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 10.16 [1.44, 71.65] |
| 1.9 Mean change Pseudomonas density in cfu/g at end of course Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.9.1 at 10 to 14 days | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.10 Number resistant strains of Pseudomonas aeruginosa Show forest plot | 2 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.10.1 at baseline | 2 | 140 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.83 [0.38, 1.82] |
| 1.10.2 at 10 to 14 days | 2 | 99 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.44 [0.94, 6.32] |
| 1.10.3 at 2 to 8 weeks | 2 | 76 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.44 [0.17, 1.14] |
| 1.10.4 Difference from baseline at 2 to 8 weeks | 1 | 29 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.27 [0.06, 1.18] |
| 1.11 Number adverse events Show forest plot | 2 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.11.1 local erythema / irritation | 2 | 131 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.46 [0.09, 2.36] |
| 1.11.2 generalised rash | 1 | 20 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 6.16 [0.12, 316.67] |
| 1.11.3 fever | 1 | 20 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.81 [0.05, 14.14] |
| 1.11.4 renal impairment (increased creatinine by 50%) | 1 | 80 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.54 [0.15, 15.56] |
| 1.11.5 auditory impairment | 1 | 76 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 5.86 [0.11, 305.44] |
| 1.11.6 proteinuria | 1 | 63 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 3.62 [0.68, 19.30] |
| 1.12 Number readmitted to hospital Show forest plot | 2 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.12.1 at 2 to 8 weeks | 1 | 16 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.14 [0.01, 1.30] |
| 1.12.2 in 80 days | 1 | 76 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.30 [0.12, 0.73] |
| 1.13 Mean time to next course of antibiotics (weeks) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.14 Mean Schwachman score at end of course Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.15 Mean WBC count at end of course Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.15.1 at 10 to 14 days | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
