Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial

Hendrik Harms, Konstantin Prass, Christian Meisel, Juliane Klehmet, Witold Rogge, Christoph Drenckhahn, Jos Göhler, Stefan Bereswill, Ulf Göbel, Klaus Dieter Wernecke, Tilo Wolf, Guy Arnold, Elke Halle, Hans-Dieter Volk, Ulrich Dirnagl, Andreas Meisel, Hendrik Harms, Konstantin Prass, Christian Meisel, Juliane Klehmet, Witold Rogge, Christoph Drenckhahn, Jos Göhler, Stefan Bereswill, Ulf Göbel, Klaus Dieter Wernecke, Tilo Wolf, Guy Arnold, Elke Halle, Hans-Dieter Volk, Ulrich Dirnagl, Andreas Meisel

Abstract

Background: Pneumonia is a major risk factor of death after acute stroke. In a mouse model, preventive antibacterial therapy with moxifloxacin not only prevents the development of post-stroke infections, it also reduces mortality, and improves neurological outcome significantly. In this study we investigate whether this approach is effective in stroke patients.

Methods: Preventive ANtibacterial THERapy in acute Ischemic Stroke (PANTHERIS) is a randomized, double-blind, placebo-controlled trial in 80 patients with severe, non-lacunar, ischemic stroke (NIHSS>11) in the middle cerebral artery (MCA) territory. Patients received either intravenous moxifloxacin (400 mg daily) or placebo for 5 days starting within 36 hours after stroke onset. Primary endpoint was infection within 11 days. Secondary endpoints included neurological outcome, survival, development of stroke-induced immunodepression, and induction of bacterial resistance.

Findings: On intention-to treat analysis (79 patients), the infection rate at day 11 in the moxifloxacin treated group was 15.4% compared to 32.5% in the placebo treated group (p = 0.114). On per protocol analysis (n = 66), moxifloxacin significantly reduced infection rate from 41.9% to 17.1% (p = 0.032). Stroke associated infections were associated with a lower survival rate. In this study, neurological outcome and survival were not significantly influenced by treatment with moxifloxacin. Frequency of fluoroquinolone resistance in both treatment groups did not differ. On logistic regression analysis, treatment arm as well as the interaction between treatment arm and monocytic HLA-DR expression (a marker for immunodepression) at day 1 after stroke onset was independently and highly predictive for post-stroke infections.

Interpretation: PANTHERIS suggests that preventive administration of moxifloxacin is superior in reducing infections after severe non-lacunar ischemic stroke compared to placebo. In addition, the results emphasize the pivotal role of immunodepression in developing post-stroke infections.

Trial registration: Controlled-Trials.com ISRCTN74386719.

Conflict of interest statement

Competing Interests: HH, AM, KP, UD, EH, SB, and CM received speakers' honoraria from Bayer Vital GmbH. A patent application on anti-infective agents and immunmodulators used for preventive therapy following an acute cerebrovascular accident has been filed to the European Patent Office (PCT/EP03/02246); Patent owner: Charité Universitaetsmedizin Berlin; Patent inventors: AM, CM, KP, EH, UD.

Figures

Figure 1. PANTHERIS trial profile.
Figure 1. PANTHERIS trial profile.
Figure 2. Time course of CRP serum…
Figure 2. Time course of CRP serum concentration.
Time course of CRP levels in placebo and verum group shown by boxplots. Number of patients is indicated by N. CRP levels in the moxifloxacin group are significant lower compared to the placebo group. The p-values for the main effects are p<0.05; ** p<0.005).
Figure 3. Kaplan-Meier curves of survival in…
Figure 3. Kaplan-Meier curves of survival in both treatment groups.
Crosses indicate time points when patients were lost to follow-up (‘censored’; n = 7; verum n = 3, placebo n = 4 placebo). Seven (verum n = 3, placebo n = 4) of 79 patients (8.9%) died within 11 days after stroke onset. Within 6 month after stroke 13 (verum n = 6, placebo n = 7) of 72 patients (18.1%) died.
Figure 4. Kaplan-Meier curves of survival in…
Figure 4. Kaplan-Meier curves of survival in patients with and without infections.
Crosses indicate time points when patients were lost to follow-up (‘censored’; n = 7, infection n = 1, no infection n = 6). Seven (no infection n = 5, infection n = 2) of 79 patients (8.9%) died within 11 days after stroke onset. Within 6 month after stroke 13 (infection n = 6, no infection n = 7) of 72 patients (18.1%) died.
Figure 5. Time course in monocytic HLA-DR…
Figure 5. Time course in monocytic HLA-DR expression after stroke.
a: Monocytic HLA-DR expression is significantly reduced in all patients at days 1, 3, and 8 compared to 90 and 180 days after stroke (*** p<0.001). b: The time course of monocytic HLA-DR expression is not significantly different between patients from the placebo and verum groups. Dashed lines indicate the upper and lower reference range for monocytic HLA-DR levels in healthy individuals (5% percentile = 18036 mAb/cell; 95% percentile = 57958 mAb/cell).
Figure 6. Monocytic HLA-DR expression in patients…
Figure 6. Monocytic HLA-DR expression in patients with and without infections.
a: In the placebo group, monocytic HLA-DR expression in patients with infections is significantly reduced compared to patients without infections at day 1 (** p = 0.003), 3 (** p = 0.005), and 8 (*** p<0.001) days, but not at day 180 after stroke. b: In the verum group, monocytic HLA-DR expression is not significantly different between patients with and without infections. Dashed lines indicate the upper and lower reference range for monocytic HLA-DR levels in healthy individuals (5% percentile = 18036 mAb/cell; 95% percentile = 57958 mAb/cell).

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