Sensitivity analyses
To perform sensitivity analysis for the outcome of mortality rate, we
excluded the study by Fouda et al. as this RCT was not explicitly
indicating the infection status of patients in the exclusion criterion.
This analysis did not change the results significantly, suggesting they
were relatively stable. (Supplementary Materials Figure S3).
For the proportion of patients with mRS ≤ 2 points, the heterogeneity
was decreased (P = 0.31, I2 = 15%) and the
results were not changed by excluding the Lampl et al. study.
(Supplementary Materials Figure S4).
Discussion
This systematic review and
meta-analysis revealed that prophylactic antibiotics could not reduce
the mortality rate and pneumonia of stroke patients, nor could they
improve functional outcomes, and length of hospital stay. However, we
find a significant reduction in infection and urinary tract infection
after stroke without increasing the incidence of adverse events.
Several factors might influence the result. First of all, the duration
of prophylactic antibiotics was insufficient. Finlayson et al. found
pneumonia was associated with longer hospitalization.25 And a retrospective study revealed that the length
of hospitalization was a strong predictor for post-stroke pneumonia, the
incidence of pneumonia for patients with hospitalization for more than
two weeks was 3.9 times more than that for patients hospitalized for
four days to one week [OR 3.90 (95%CI: 3.73-4.08, P <
0.0001)]. 26 Among the RCTs included in this
meta-analysis, 9-11 the mean length of hospital stay
in the prophylactic antibiotics group was 23.5 days, but the use of
prophylactic antibiotics was only two to seven days. Therefore, it was
difficult to avoid the occurrence of pneumonia in stroke patients
throughout the treatment. In particular, the length of the hospital stay
was too long. Second, in most studies, the time window before the start
of prophylactic antibiotic therapy was quite long-up to 24h after
stroke. To evaluate the effects of different administration times, we
performed a subgroup analysis and found a decreasing trend in pneumonia
in patients with early prophylactic use of antibiotics within 24 hours
after admission [RR 0.81 (95%CI: 0.62-1.07,I2 = 0%)] as compared with those using
prophylactic use of antibiotics within 48 hours after admission [RR
0.94 (95%CI: 0.79-1.11, I2 = 0%)]. Third,
the severity of stroke is a risk factor for infection after stroke.27 Thus, patients with severe stroke who are at high
risk for infection should be considered for prophylactic antibiotics.
However, an RCT with a large sample size included in our meta-analysis
involved patients with mild stroke, and the average hospital stay of
patients was only 6.35 days. 10 Considering the low
incidence of nosocomial infection, 26 the role of
prophylactic antibiotics in reducing post-stroke infection was not fully
reflected.
Stroke-related infections, particularly pneumonia, are regarded as an
independent risk factor associated with mortality after stroke.1 The results of this study did not find a reduction
in pneumonia, so the mortality rate was not significantly reduced.
In two studies, 12,22 fluoroquinolones were used as
prophylactic antibiotics for post-stroke infection. There concerns about
the adverse events of fluoroquinolones on the nervous system.
However, no serious adverse
events were reported in these two studies. And several preclinical
studies had described the neuroprotective effects of moxifloxacin after
transient focal brain ischemia. 28Nevertheless, attention still
should be paid to the adverse events in the clinical application of
fluoroquinolones.
There are several strengths in this meta-analysis. First, compared with
previous studies, 7,8,29 this meta-analysis included
more RCTs and sample size; thus, the confidence interval of the study
and the heterogeneity between studies for each outcome were reduced.
Second, we performed a subgroup analysis by time to the first dose of
antibiotic drugs. We found that patients with early prophylactic use of
antibiotics within 24 hours after admission had a decreasing trend in
mortality and pneumonia compared with those with prophylactic use of
antibiotics within 48 hours. Third, we assessed the overall evidence
according to the GRADE quality of evidence approach.
However, this study still has some limitations. First, the outcomes of
patients with post-acute stroke infection might be impacted by stroke
severity, chronic conditions, dysphagia, age, invasive procedure,
different timings, types, and duration of antimicrobial use.30,31 The invasion procedures, such as urinary
catheterization or mechanical ventilation, could increase the risk of
infection by facilitating the entry of a pathogen; However, we could not
perform these subgroup analyses due to unavailable data. For example,
only one RCT in our meta-analysis described the use of urinary
catheterization, 12 so we could not evaluate the
effect of urinary catheterization on prophylactic antibiotics. Secondly,
clinical heterogeneity is inevitable due to different criteria used for
infection in RCTs; therefore, the results of this meta-analysis should
be interpreted with caution. Thirdly, most of the RCTs included in this
study were performed in developed countries with standard stroke units.
Due to the differences in medical resources and nursing levels between
developing and developed countries, standard stroke unit management is
unconditionally carried out in some places, and the medical environment
is poor, 32,33 which increases the incidence of
infection in patients. Evidence for prophylactic antibiotics in stroke
patients is lacking in developing countries or remote areas. Therefore,
whether to recommend prophylactic antibiotics in patients with
post-acute stroke infection needs to be further confirmed by large-scale
RCTs.