Tratamiento intravenoso con antibióticos antipseudomonas solos versus combinados para personas con fibrosis quística
Appendices
Appendix 1. Electronic search strategies
| Database | Search strategy | Date searched |
|---|---|---|
| US National Institutes of Health Ongoing Trials Register Clinicaltrials.gov | [Advanced Search] CONDITION/ DISEASE: Cystic Fibrosis OTHER TERMS: (Antibiotic OR antibacterial) AND intravenous AND (Pseudomonas aeruginosa OR P. aeruginosa) STUDY TYPE: Interventional Studies | 16 November 2020 |
| World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) | [Advanced Search Form] CONDITION: cystic fibrosis INTERVENTION: intravenous OR IV RECRUITMENT STATUS: All | database unavailable due to Covid‐19 pandemic |
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. |
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| 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 | |
