Martha Vargas

The Early Systemic Prophylaxis of Infection After Stroke Study: A Randomized Clinical Trial

Background and Purpose— Early infection after stroke is frequent but the clinical value of antibiotic prophylaxis in acute stroke has never been explored. Objective and Methods— The Early Systemic Prophylaxis of Infection After Stroke (ESPIAS) is a randomized, double-blind, placebo-controlled study of antibiotic prophylaxis in patients older than 18 years with nonseptic ischemic or hemorrhagic stroke enrolled within 24 hours from clinical onset. Interventions included intravenous levofloxacin (500 mg/100 mL/d, for 3 days) or placebo (0.9% physiological serum) in addition to optimal care. A sample size of 240 patients was calculated to identify a 15% absolute risk reduction of the primary outcome measure, which was the incidence of infection at day 7 after stroke. Secondary outcome measures were neurological outcome and mortality at day 90. Results— Based on a preplanned futility analysis, the study was interrupted prematurely when 136 patients had been included. Levofloxacin and placebo patients had a cumulative rate of infection of 6% and 6% (P=0.96) at day 1; 10% and 12% (P=0.83) at day 2; 12% and 15% (P=0.66) at day 3; 16% and 19% (P=0.82) at day 7; and 30% and 33% (P=0.70), at day 90. Using logistic regression, favorable outcome at day 90 was inversely associated with baseline National Institutes of Health Stroke Scale (OR, 0.72; 95% CI, 0.59 to 0.89; P=0.002) and allocation to levofloxacin (OR, 0.19; 95% CI, 0.04 to 0.87; P=0.03). Conclusions— Prophylactic administration of levofloxacin (500 mg/100 mL/day for 3 days) is not better than optimal care for the prevention of infections in patients with acute stroke.

Aeromonas spp. and traveler's diarrhea: clinical features and antimicrobial resistance.

Traveler’s diarrhea is the most common health problem of international travelers. We determined the prevalence of Aeromonas spp. associated with traveler’s diarrhea and analyzed the geographic distribution, clinical features, and antimicrobial susceptibility. Aeromonas spp. were isolated as a cause of traveler’s diarrhea in 18 (2%) of 863 patients. A. veronii biotype sobria was isolated in nine patients, A. caviae in seven patients, and A. jandai and A. hydrophila in one patient each. Aeromonas spp. were isolated with a similar prevalence in Africa, Latin America, and Asia. Watery and persistent diarrhea, fever, and abdominal cramps were common complaints. All strains were resistant to ampicillin; showed variable resistance to chloramphenicol, tetracycline, and cotrimoxazole; and were susceptible to cefotaxime, ciprofloxacin, and nalidixic acid. The persistence of symptoms made antimicrobial treatment necessary.

Catecholamines, infection, and death in acute ischemic stroke

Experimental studies have recently suggested that acute ischemia may facilitate the appearance of fatal infections as part of a brain-induced immunodepression syndrome. However, the mechanisms and neurological consequences of infections complicating acute ischemic stroke have received much less attention at the bedside. The incidence of infection and death after non-septic stroke was compared in this prospective study with longitudinal changes of cytokines, leukocytes, normetanephrine (NMN) and metanephrine (MN) in 75 consecutive patients. In multivariate analysis, infection, n = 13 (17%), was associated with the upper quartile of MN (OR 3.51, 95% CI 1.30-9.51), neurological impairment (NIHSS) on admission (OR 3.99, 95% CI 1.34-11.8), monocyte count (OR 1.78, 95% CI 1.13-2.79), and increased interleukin (IL)-10 (OR 1.54, 95% CI 1.00-2.38). Mortality at 3 months, n = 16 (21%), was associated with increased levels of NMN on admission (OR 2.34 95% CI 1.15-4.76), NIHSS score (OR 2.57, 95% CI 1.29-5.11), and higher IL-6 levels (OR 1.29, 95% 1.00-1.67). These findings suggest that acute ischemic stroke is associated with an early activation of the sympathetic adrenomedullar pathway that lowers the threshold of infection and increases the risk of death. Moreover, these findings are independent of the blood borne effects of pro- and anti-inflammatory cytokines, and circulating leukocytes.

Interleukin 10, monocytes and increased risk of early infection in ischaemic stroke

Background and purpose: : The pathophysiology of stroke-associated infection (SAI) is uncertain. The cytokine profile and peripheral white cell response were assessed in patients with or without SAI. Methods: The incidence of SAI was assessed in 110 patients with ischaemic stroke allocated antibiotic prophylaxis or placebo within 24 h of clinical onset. Peripheral white cell counts, interleukin (IL)6, tumour necrosis factor (TNF)α and IL10 were measured in plasma. Results: 17 (15%) patients developed infection and showed time-dependent increases of total white cell count, neutrophils, monocytes, lymphocytes, IL6 and IL10, whereas TNFα and the TNFα/IL10 ratio decreased. In logistic regression, IL10 (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.01 to 1.16), monocyte count (OR 1.42, 95% CI 1.08 to 1.87) and National Institute for Health Stroke Survey score on admission (OR 1.17, 95% CI 1.05 to 1.31) were independent predictors of systemic infection. Conclusions: SAI is associated with stroke severity, excessive IL10-mediated response and an increased number of circulating monocytes. These results support the finding that acute ischaemic brain injury triggers a blood-borne anti-inflammatory response that decreases the antimicrobial drive of the immune system.

Uric Acid Levels Are Relevant in Patients With Stroke Treated With Thrombolysis

Background and Purpose— Uric acid (UA) is a neuroprotective antioxidant that improves the benefits of alteplase in experimental ischemia. However, it is unknown whether endogenous UA also influences the response to thrombolysis in patients with stroke. Methods— A total of 317 consecutive patients treated with thrombolysis were included in a prospective stroke registry. Demographics, laboratory data, neurological course, and infarction volume were prospectively collected. Excellent outcome was defined as achieving a modified Rankin Scale score <2 at 90 days. Binary and ordinal logistic regression models were used to analyze modified Rankin Scale score at 90 days. Results— UA levels were significantly higher in patients with an excellent outcome than in patients with a poor outcome (5.82 [1.39] versus 5.42 [1.81], P=0.029). In multivariate models, increased UA levels (OR, 1.23; 95% CI, 1.03 to 1.49; P=0.025) were associated with an excellent outcome and with an increased risk of shifting to a better category across the modified Rankin Scale (OR, 1.19; 95% CI, 1.04 to 1.38; P=0.014) independently of the effect of confounders. The levels of UA and the volume of final infarction were inversely correlated (r=−0.216, P<0.001) and the inverse correlation remained after adjustment for age, sex, and baseline National Institutes of Health Stroke Scale score (t value=−2.54, P=0.01). Significantly lower UA levels were found in patients with malignant middle cerebral artery infarction and parenchymal hemorrhage postthrombolysis. Conclusions— Increased UA serum levels are associated with better outcome in patients with stroke treated with reperfusion therapies. These results support the assessment of the potential neuroprotective role of the exogenous administration of UA in patients with stroke treated with thrombolysis.

Enteroaggregative Escherichia coli Virulence Factors in Traveler's Diarrhea Strains

Enteroaggregative Escherichia coli (EAEC) is associated with diarrhea in Spanish travelers to developing countries. In this study, the polymerase chain reaction was used to test EAEC isolates for genes encoding putative virulence factors, including EAEC adhesins, the plasmid-encoded toxin (Pet), a heat-stable enterotoxin (EAST), and Shigella enterotoxins 1 and 2 (ShET1 and ShET2). Findings included a low prevalence of genes for Pet (4.3%), ShET2 (4.3%), and the adherence factor AAF/II (8.7%). The overlapping genes encoding the ShET1 and the Pic mucinase were present in most EAEC strains tested (56.5%); however, some strains that carried this locus did not produce both proteins, as determined by Western immunoblot. Surprisingly, ShET1 and ShET2 genes were also found in other E. coli pathotypes, as was the EAST toxin locus. These findings underscore the heterogeneity of EAEC strains and suggest that the ShET1 may be an important virulence factor in travelers diarrhea.

Enteroaggregative Escherichia coli Strains as a Cause of Traveler's Diarrhea: A Case-Control Study

To elucidate the importance of enteroaggregative Escherichia coli (EAggEC) strains as a cause of travelers diarrhea in Spanish travelers, a prospective case-control 1:1 study was done in a university hospital clinic for travelers. EAggEC strains were isolated from 23 of 165 case-patients and from 4 of 165 controls (P = .0003). In 16 patients, this was the only isolate recovered. Six of the EAggEC-positive isolates from the case-patients and 2 from the controls were positive for the enteroaggregative stable toxin type 1 gene. Other enteropathogens were also isolated. Shigella and enterotoxigenic E. coli strains showed significant differences between cases and controls (P = .0023 and P < .0001, respectively). Geographic distribution of the EAggEC strains was homogeneous, and the clinical symptom, secretory diarrhea, did not differ statistically with that for the enterotoxigenic E. coli strains. EAggEC strains are a cause of secretory diarrhea in Spaniards traveling to developing countries.

Quinolone Resistance in Enterotoxigenic Escherichia coli Causing Diarrhea in Travelers to India in Comparison with Other Geographical Areas

ABSTRACT Enterotoxigenic Escherichia coli isolates were identified as a cause of travelers diarrhea in 82 of 520 (16%) patients and tested for resistance to seven antimicrobial agents. Thirty patients (36%) needed antimicrobial therapy: 17 (56%) for persistence of symptoms and 13 (44%) for severity of symptoms. Ampicillin, tetracycline, and trimethoprim-sulfamethoxazole resistance was high. Chloramphenicol showed moderate activity, and amoxicillin plus clavulanic acid, nalidixic acid, and ciprofloxacin showed very good activity. Five nalidixic acid-resistant strains were isolated, four from patients visiting India.

Multimodal CT-Assisted Thrombolysis in Patients With Acute Stroke A Cohort Study

Background and Purpose— The value of multimodal CT to assist thrombolysis has received little attention in stroke. Methods— We assessed prospectively the impact derived from the routine application of CT perfusion and CTA in patients with acute stroke treated consecutively with alteplase. The safety and efficacy of thrombolytic therapy were compared in 106 patients assisted with CT/CTA/CT perfusion (multimodal CT group) and 262 patients assisted without full multimodal brain imaging (control group) during a 5-year period (2005–2009). Results— Good outcome (modified Rankin scale score ≤2) at 3 months was increased in the multimodal group compared with controls (adjusted OR, 2.88; 95% CI, 1.50–5.52). Multimodal-assisted thrombolysis yielded superior benefits in patients treated beyond 3 hours (adjusted OR, 4.48; 95% CI, 1.68–11.98) than treated within 3 hours (adjusted OR, 1.31; 95% CI, 0.80–2.16; interaction test P=0.043). Mortality (14% and 15%) and symptomatic hemorrhage (5% and 7%) were similar in both groups. Conclusions— Multimodal CT use in routine clinical practice may heighten the overall efficacy of thrombolytic therapy in acute ischemic stroke. The benefits seem greater in patients treated >3 hours after stroke onset, but further randomized clinical trials are needed to confirm these findings.

In vitro activity of rifaximin against enteropathogens producing traveler's diarrhea

Nowadays, around 40 to 60% of Spanish travelers to developing countries develop diarrhea (4). Different enteropathogens have been associated with the development of travelers diarrhea. The levels of prevalence of these enteropathogens as a cause of travelers diarrhea are 42% for diarrheagenic Escherichia coli, 19.4% for Shigella spp., 3% for Salmonella spp., 2% for Campylobacter spp., 2% for Yersinia spp., 2% for Aeromonas spp., and <2% for others (4). Infectious diarrhea is usually a self-limited disease lasting a few days and does not require antibiotic therapy. In some cases, antimicrobial therapy is recommended (2); however, high levels of resistance to several antimicrobial agents have been described. To resolve the problem of this increase in resistance, the activities of new antimicrobial agents should be studied. Rifaximin is a nonabsorbable antibiotic (2, 5, 6) achieving concentrations of 4,000 to 8,000 μg/g in feces, with a common therapeutic dosage being 800 mg divided in two oral administrations (7). The main aim of this study was to evaluate the in vitro activity of rifaximin against enteropathogens isolated as a cause of travelers diarrhea. MICs of several antimicrobial agents for 177 enteropathogens (Table ​(Table1)1) were determined by the agar dilution method according to guidelines of the National Committee for Clinical Laboratory Standards (8). E. coli ATCC 29522 was used as a quality control strain. TABLE 1 MIC50s, MIC90s, and percentages of resistance of each antimicrobial agent for different enteropathogensa MICs at which 50 and 90% of the isolates tested were inhibited (MIC50s and MIC90s, respectively) and the percentages of resistance were calculated for each antimicrobial agent used in this study and are shown in Table ​Table11. The conventional antimicrobial agents, such as ampicillin, cotrimoxazole, tetracycline, and chloramphenicol, showed no or very little activity against the enteropathogens producing travelers diarrhea. A MIC90 of ampicillin of greater than 128 μg/ml was observed against all of the microorganisms, whereas the MIC90s of tetracycline and trimethoprim for all the microorganisms were ≥16 μg/ml. Only nalidixic acid and ciprofloxacin showed MIC90s of 256 and 32 μg/ml, respectively. The MIC90s of chloramphenicol for the different microorganisms were in a range from 8 to >128 μg/ml. Cotrimoxazole and ampicillin have been widely used to treat travelers diarrhea (3, 11, 12), and the long use and sometimes the misuse of these antibiotics have been associated with the increase of resistance levels (1, 10, 12). MIC50s and MIC90s of rifaximin and rifampin were very similar. MICs of rifaximin ranged from 4 to 8 and from 4 to 16 μg/ml, and MICs of rifampin ranged from 4 to 16 and from 8 to 16 μg/ml, for all tested bacteria except Yersinia enterocolitica and C. jejuni. In particular, the MIC50 and MIC90 of rifamixin of 64 and 128 μg/ml, respectively, were observed for Y. enterocolitica and a value of >128 μg/ml for both the MIC50 and MIC90 was achieved for C. jejuni. In this case and only for rifaximin, doses greater than 128 μg/ml were tested to determine the precise MIC50s and MIC90s, which were found to be 256 and 512 μg/ml, respectively. The in vitro activities of rifaximin against strains from stock culture collections of four university-associated teaching hospitals had been previously reported by Hoover et al. (6). In that study, the activities of rifaximin against enteropathogens were found to be as follows: a MIC50 of 4 to 8 μg/ml and a MIC90 of >8 μg/ml. These results are in accordance with ours, even though our strains were isolated from patients who traveled to different geographical areas. In another study, Ripa et al. (9) tested rifaximin against Campylobacter and Yersinia strains collected from patients with diarrhea. The main difference between these studies and ours is the MICs of rifaximin for Y. enterocolitica and C. jejuni, two microorganisms which were isolated from not more than 2% of patients with travelers diarrhea in our laboratory (3). In conclusion, rifaximin is a nonabsorbable antimicrobial agent, reaching high concentrations in the intestinal tract. The concentrations of rifaximin achieved in the intestinal tract are more than 10-fold higher than the MICs of this antimicrobial agent for the different enteropathogens used in our study. In particular, we observed a definitely good in vitro activity of rifaximin against several enteropathogens, such as E. coli, Shigella spp., and Salmonella spp., which is in accordance with clinical and microbiological outcomes of two recent studies of travelers diarrhea (2; H. L. DuPont, Z. D. Jiang, C. D. Ericsson, J. J. Mathewson, J. Aldachi, E. Palazini, L. S. Riopel, D. Ashley, and F. Martinez-Sandoval, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 2227, p. 698, 1999).