To assess whether a potential benefit with combination antibiotic therapy is restricted to the most critically ill subset of patients, particularly those with septic shock. OVID MEDLINE (1950–October 2009), EMBASE (1980–October 2009), the Cochrane Central Register of Controlled Trials (to third quarter 2009), the ClinicalTrial.gov database, and the SCOPUS database. Randomized or observational studies of antimicrobial therapy of serious bacterial infections potentially associated with sepsis or septic shock. Fifty studies met entry criteria. Study design, mortality/clinical response, and other variables were extracted independently by two reviewers. When possible, study datasets were split into mutually exclusive groups with and without shock or critical illness. Although a pooled odds ratio indicated no overall mortality/clinical response benefit with combination therapy (odds ratio, 0.856; 95% confidence interval, 0.71–1.03; p = .0943; I2 = 45.1%), stratification of datasets by monotherapy mortality risk demonstrated substantial benefit in the most severely ill subset (monotherapy risk of death >25%; odds ratio of death, 0.51; 95% confidence interval, 0.41–0.64; I2 = 8.6%). Of those datasets that could be stratified by the presence of shock/critical illness, the more severely ill group consistently demonstrated increased efficacy of a combination therapy strategy (odds ratio, 0.49; 95% confidence interval, 0.35–0.70; p < .0001; I2 = 0%). An increased risk of death was found in low-risk patients (risk of death ≤15% in the monotherapy arm) exposed to combination therapy (odds ratio, 1.53; 95% confidence interval, 1.16–2.03; p = .003; I2 = 8.2%). Meta-regression indicated that efficacy of combination therapy was dependent only on the risk of death in the monotherapy group. Combination antibiotic therapy improves survival and clinical response of high-risk, life-threatening infections, particularly those associated with septic shock but may be detrimental to low-risk patients.

Objective Previous observational studies suggest that the use of proton pump inhibitors (PPIs) may increase the risk of hospitalisation for community-acquired pneumonia (HCAP). However, the potential presence of confounding and protopathic biases limits the conclusions that can be drawn from these studies. Our objective was, therefore, to examine the risk of HCAP with PPIs prescribed prophylactically in new users of non-steroidal anti-inflammatory drugs (NSAIDs). Design We formed eight restricted cohorts of new users of NSAIDs, aged ≥40 years, using a common protocol in eight databases (Alberta, Saskatchewan, Manitoba, Ontario, Quebec, Nova Scotia, US MarketScan and the UK's General Practice Research Database (GPRD)). This specific patient population was studied to minimise bias due to unmeasured confounders. High-dimensional propensity scores were used to estimate site-specific adjusted ORs (aORs) for HCAP at 6 months in PPI patients compared with unexposed patients. Fixed-effects meta-analytic models were used to estimate overall effects across databases. Results Of the 4 238 504 new users of NSAIDs, 2.3% also started a PPI. The cumulative 6-month incidence of HCAP was 0.17% among patients prescribed PPIs and 0.12% in unexposed patients. After adjustment, PPIs were not associated with an increased risk of HCAP (aOR=1.05; 95% CI 0.89 to 1.25). Histamine-2 receptor antagonists yielded similar results (aOR=0.95, 95% CI 0.75 to 1.21). Conclusions Our study does not support the proposition of a pharmacological effect of gastric acid suppressors on the risk of HCAP.

Introduction: Despite recent advances in the management of septic shock, mortality remains unacceptably high. Earlier initiation of key therapies including appropriate antimicrobials and fluid resuscitation appears to reduce the mortality in this condition. This study examined whether early initiation of vasopressor therapy is associated with improved survival in fluid therapy-refractory septic shock. Methods: Utilizing a well-established database, relevant information including duration of time to vasopressor administration following the initial documentation of recurrent/persistent hypotension associated with septic shock was assessed in 8,670 adult patients from 28 ICUs in Canada, the United States of America, and Saudi Arabia. The primary endpoint was survival to hospital discharge. Secondary endpoints were length of ICU and hospital stay as well as duration of ventilator support and vasopressor dependence. Analysis involved multivariate linear and logistic regression analysis. Results: In total, 8,640 patients met the definition of septic shock with time of vasopressor/inotropic initiation documented. Of these, 6,514 were suitable for analysis. The overall unadjusted hospital mortality rate was 53%. Independent mortality correlates included liver failure (odds ratio (OR) 3.46, 95% confidence interval (CI), 2.67 to 4.48), metastatic cancer (OR 1.63, CI, 1.32 to 2.01), AIDS (OR 1.91, CI, 1.29 to 2.49), hematologic malignancy (OR 1.88, CI, 1.46 to 2.41), neutropenia (OR 1.78, CI, 1.27 to 2.49) and chronic hypertension (OR 0.62 CI, 0.52 to 0.73). Delay of initiation of appropriate antimicrobial therapy (OR 1.07/hr, CI, 1.06 to 1.08), age (OR 1.03/yr, CI, 1.02 to 1.03), and Acute Physiology and Chronic Health Evaluation (APACHE) II Score (OR 1.11/point, CI, 1.10 to 1.12) were also found to be significant independent correlates of mortality. After adjustment, only a weak correlation between vasopressor delay and hospital mortality was found (adjusted OR 1.02/hr, 95% CI 1.01 to 1.03, P 14.1 hours). There was no significant relationship of vasopressor initiation delay to duration of vasopressor therapy (P = 0.313) and only a trend to longer duration of ventilator support (P = 0.055) among survivors. Conclusion: Marked delays in initiation of vasopressor/inotropic therapy are associated with a small increase in mortality risk in patients with septic shock.

Dipeptidylpeptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists are incretin-based drugs that are widely used in the treatment of type 2 diabetes. Despite lowering the risk of hypoglycemia and having favorable effects on body weight compared with other antidiabetic drugs,¹ there have been concerns that the use of incretin-based drugs may increase the risk of pancreatic-related events. Indeed, analyses^2-4 of adverse events databases have associated the use of incretin-based drugs with an increased risk of acute pancreatitis, although such analyses have well-known limitations. In addition, in a meta-analysis⁵ of randomized clinical trials (RCTs), incretin-based drugs were associated with an increased risk of pancreatic enzyme level elevation, but the association with acute pancreatitis was inconclusive because of sparse data. This association was also assessed in several observational studies, but these have generated conflicting findings.^6-23 Such discrepancies may be the result of important methodologic limitations, such as confounding by indication, and none were adequately powered to detect a modest increased risk of this rare outcome.²⁴