Contemporary outcomes of left thoraco-abdominal esophagectomy due to cancer in the esophagus or gastroesophageal junction, a multicenter cohort study.

Surgery for cancer of the esophagus or gastro-esophageal junction can be performed with a variety of minimally invasive and open approaches. The left thoracoabdominal esophagectomy (LTE) is an open technique that gives an opportunity to operate in the chest and abdomen with excellent exposure of the gastro-esophageal junction through a single incision, and there is currently no equivalent minimally invasive technique available. The aim of this multi-institutional review was to study a large contemporary international study cohort of patients treated with LTE. An international multicenter cohort study was performed including all patients treated with LTE at six high-volume centers for gastro-esophageal cancer surgery between 2012 and 2022. Patient data were prospectively collected in each participating centers' institutional database. Information about patient, tumor, and treatment details were collected. The study cohort included a total of 793 patients treated with LTE during the study period. The most frequently observed complications were pneumonia in 185/727 (25.5%) patients and atrial fibrillation in 91/727 (12.5%). Anastomotic leak occurred in 35/727 (4.8%) patients; no patient suffered from conduit necrosis. Thirty-day mortality occurred in 15/785 (1.9%) patients and 90-day mortality in 39/785 (5.0%) patients. Factors with statistically significant association with survival were American Society for Anesthesiologists-score, tumor location, tumor stage, and tumor free resection margins. Neoadjuvant therapy was not associated with increased survival compared to surgery alone but neoadjuvant chemoradiotherapy compared to neoadjuvant chemotherapy showed statistically significant improved survival with hazard ratio 0.60 (95% confidence intervals:0.44-0.80, P = 0.001) in a multivariable adjusted model. This study demonstrates that LTE can be applied in selected patients with results that are comparable to other large studies of open and minimally invasive surgery for esophageal or gastro-esophageal cancer at high-volume centers.

ERAS guidelines-driven upper gastrointestinal contrast study after esophagectomy can detect delayed gastric conduit emptying and improve outcomes.

BACKGROUND: Delayed gastric conduit emptying can occur after esophagectomy and has been shown to be associated with increased risk for postoperative complications. Application of a standardized clinical protocol after esophagectomy including an upper gastrointestinal contrast study has the potential to improve postoperative outcomes. METHODS: Prospective cohort including all patients operated with esophagectomy at two high-volume centers for esophageal surgery. The standardized clinical protocol included an upper gastrointestinal contrast study on day 2 or 3 after surgery. All images were compiled and evaluated for the purpose of the study. Clinical data was collected in IRB approved institutional databases at the participating centers. RESULTS: The study included 119 patients treated with esophagectomy of whom 112 (94.1%) completed an upper gastrointestinal contrast study. The results showed that 8 (7.1%) patients had radiological delayed gastric conduit emptying defined as no emptying of contrast through the pylorus. Partial conduit emptying was seen in 34 (30.4%) patients, and 70 (62.5%) patients had complete conduit emptying. Complete or partial emptying was associated with significantly earlier nasogastric tube removal (3 vs. 6 days) and hospital discharge 8 vs. 17 days, P < 0.001). Radiological signs of delayed gastric conduit emptying were shown to be associated with increased risk of postoperative complications. There was, however, no association with severe postoperative complications according to Clavien-Dindo score, pulmonary complications, anastomotic leak or need for intensive care. CONCLUSION: The results of the study demonstrate that postoperative upper gastrointestinal contrast studies can be used to assess the level of emptying of the gastric conduit after esophagectomy. Application of upper gastrointestinal contrast study in the ERAS guidelines-driven standardized clinical pathway after esophagectomy has the potential to improve postoperative outcomes.

Fit-for-Discharge Criteria after Esophagectomy: An International Expert Delphi Consensus.

There are no internationally recognized criteria available to determine preparedness for hospital discharge after esophagectomy. This study aims to achieve international consensus using Delphi methodology. The expert panel consisted of 40 esophageal surgeons spanning 16 countries and 4 continents. During a 3-round, web-based Delphi process, experts voted for discharge criteria using 5-point Likert scales. Data were analyzed using descriptive statistics. Consensus was reached if agreement was ≥75% in round 3. Consensus was achieved for the following basic criteria: nutritional requirements are met by oral intake of at least liquids with optional supplementary nutrition via jejunal feeding tube. The patient should have passed flatus and does not require oxygen during mobilization or at rest. Central venous catheters should be removed. Adequate analgesia at rest and during mobilization is achieved using both oral opioid and non-opioid analgesics. All vital signs should be normal unless abnormal preoperatively. Inflammatory parameters should be trending down and close to normal (leucocyte count ≤12G/l and C-reactive protein ≤80 mg/dl). This multinational Delphi survey represents the first expert-led process for consensus criteria to determine 'fit-for-discharge' status after esophagectomy. Results of this Delphi survey may be applied to clinical outcomes research as an objective measure of short-term recovery. Furthermore, standardized endpoints identified through this process may be used in clinical practice to guide decisions regarding patient discharge and may help to reduce the risk of premature discharge or prolonged admission.

Diagnostic criteria and symptom grading for delayed gastric conduit emptying after esophagectomy for cancer: international expert consensus based on a modified Delphi process.

Delayed gastric conduit emptying (DGCE) after esophagectomy for cancer is associated with adverse outcomes and troubling symptoms. Widely accepted diagnostic criteria and a symptom grading tool for DGCE are missing. This hampers the interpretation and comparison of studies. A modified Delphi process, using repeated web-based questionnaires, combined with live interim group discussions was conducted by 33 experts within the field, from Europe, North America, and Asia. DGCE was divided into early DGCE if present within 14 days of surgery and late if present later than 14 days after surgery. The final criteria for early DGCE, accepted by 25 of 27 (93%) experts, were as follows: >500 mL diurnal nasogastric tube output measured on the morning of postoperative day 5 or later or >100% increased gastric tube width on frontal chest x-ray projection together with the presence of an air-fluid level. The final criteria for late DGCE accepted by 89% of the experts were as follows: the patient should have 'quite a bit' or 'very much' of at least two of the following symptoms; early satiety/fullness, vomiting, nausea, regurgitation or inability to meet caloric need by oral intake and delayed contrast passage on upper gastrointestinal water-soluble contrast radiogram or on timed barium swallow. A symptom grading tool for late DGCE was constructed grading each symptom as: 'not at all', 'a little', 'quite a bit', or 'very much', generating 0, 1, 2, or 3 points, respectively. For the five symptoms retained in the diagnostic criteria for late DGCE, the minimum score would be 0, and the maximum score would be 15. The final symptom grading tool for late DGCE was accepted by 27 of 31 (87%) experts. For the first time, diagnostic criteria for early and late DGCE and a symptom grading tool for late DGCE are available, based on an international expert consensus process.

Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis.

There has recently been increased interest in the assessment of body composition in patients with esophageal cancer for the purpose of nutritional evaluation and prognostication. This systematic review and meta-analysis intends to summarize and critically evaluate the current literature concerning the assessment of body composition in patients with esophageal cancer and to assess its potential implication upon early and late outcomes. A systematic literature search (up to August, 2017) was conducted for studies describing the assessment of body composition in patients with esophageal and gastroesophageal junctional cancer. Meta-analysis of postoperative outcomes including long-term survival was performed using random effects models. Twenty-nine studies reported the assessment of body composition in 3193 patients. Methods used to assess body composition in patients with esophageal cancer included computerized tomography (n = 18 studies), bioelectrical impedance analysis (n = 10), and dual-energy X-ray absorptiometry (n = 1). Significant variability was observed in regard to study design and the criteria used to define individual parameters of body composition. Sarcopenic patients had a higher incidence of postoperative pulmonary complications (7 studies, OR 2.03, 95% CI 1.32-3.11, P = 0.001) after esophagectomy. Meta-analysis of six studies presenting long-term outcomes after esophagectomy identified significantly worse survival in patients who were sarcopenic (HR 1.70, 95% CI 1.33- 2.17, P < 0.0001). The assessment of body composition has the potential to become a clinically useful tool that could support decision-making in patients with esophageal cancer. Current evidence is however weakened by inconsistencies in methods of assessing and reporting body composition in this patient group.

Defining pneumonia after esophagectomy for cancer: validation of the Uniform Pneumonia Score in a high volume center in North America.

Surgery is a central component of multimodality therapy for esophageal and gastroesophageal junction cancer. Pneumonia is a common sequela of esophagectomy, leading to an increase in intensive care unit stay, hospital stay, readmission rates, and postoperative mortality. Developing strategies to reduce pneumonia after esophagectomy is hampered by the absence of a standardized methodology for defining pneumonia. This study aims to validate the Uniform Pneumonia Score (UPS) in a high volume center in the USA. The UPS was developed to define pneumonia after esophagectomy for cancer and is based on the assessment of temperature (°C), leukocyte count (×109/L), and pulmonary radiography. The UPS has been validated utilizing a prospective, Institutional Review Board approved database of esophageal cancer patients treated in a high volume esophagectomy center in the USA between 2010 and 2015. One hundred ninety-three consecutive patients were included and 21 (10.9%) were treated for pneumonia. The UPS was able to predict treatment for suspected pneumonia with a good sensitivity (85.7%, confidence interval (CI): 63.7%-96.7%), specificity (97.1%, CI: 93.4%-99.1%), positive predictive value (78.3%, CI: 59.9%-89.7%), and negative predictive value (98.2%, CI: 95.1%-99.4%). The diagnostic accuracy was 95.9%, CI: 92.0%-98.2%. The UPS demonstrated to be a reliable scoring system to define pneumonia after esophagectomy for cancer. Global application of this model will standardize the definition of pneumonia after esophagectomy. This will improve outcome reporting and comparisons of complications between individual institutions, clinical trials, and national audits.

Enhanced recovery pathways lead to an improvement in postoperative outcomes following esophagectomy: systematic review and pooled analysis.

The aim of this systematic review and pooled analysis is to determine the effect of enhanced recovery programs (ERP) on clinical outcome measures following esophagectomy. Medline, Embase, trial registries, conference proceedings, and reference lists were searched for trials comparing clinical outcome from esophagectomy followed by a conventional pathway with esophagectomy followed by an ERP. Primary outcomes were the incidence of postoperative mortality, anastomotic leak and pulmonary complications, and secondary outcomes were length of hospital stay and the incidence of 30-day readmission. Nine studies were included comprising 1240 patients, 661 patients underwent esophagectomy followed conventional pathway, and 579 patients underwent ERP. Utilization of ERP was associated with a reduction in the incidence of anastomotic leak (12.2-8.3%; pooled odds ratios = 0.61; 95% confidence interval = 0.39 to 0.96; P = 0.03) and pulmonary complications (29.1-19.6%; pooled odds ratios = 0.52; 95% confidence interval = 0.36 to 0.77; P = 0.001) and length of hospital stay, and no significant change in postoperative mortality or readmission rate. There was significant variation in the design of enhanced recovery protocols, surgical approach, and utilization of neoadjuvant therapies between the studies that are important confounding variables to be considered. This study suggests a benefit to the utilization of ERP following esophagectomy. The pathways provide a template for all medical personnel interacting with these patients in order to provide incremental changes in all aspects of clinical care that translates into global improvements seen in postoperative outcomes.

Impact of a multidisciplinary standardized clinical pathway on perioperative outcomes in patients with oesophageal cancer.

BACKGROUND: Defined clinical pathways can contribute to improved outcomes in patients undergoing oesophageal cancer surgery. A standardized oesophagectomy clinical pathway (SOCP) established at the Virginia Mason Medical Center (VMMC) in Seattle, Washington, USA was introduced into the Royal Surrey County Hospital (RSCH), Guildford, UK in 2011. The aim of this study was to see whether transfer and implementation of an oesophagectomy care pathway could change postoperative outcomes significantly. METHODS: Three consecutively accrued study groups were examined at the RSCH: patients operated on immediately before the introduction of the SOCP (group 1), patients operated on after the introduction of the SOCP but not included in the pathway (group 2), and patients managed according to the SOCP (group 3). Outcomes were compared with those of patients who had surgery at the VMMC between 2009 and 2011 using the SOCP (group 4). RESULTS: There were 12 patients in each of the first three groups and 74 in group 4. All groups were similar with respect to body mass index, medical co-morbidities and clinical stage. The median age of patients in group 3 was significantly lower than that in group 1, and median American Society of Anesthesiologists score was significantly better in group 3 compared with group 4. Following initiation of the SOCP there was an increase in immediate extubation (8 of 12 in group 1 versus 12 of 12 in group 3) and first-day mobilization (1 of 12 versus 12 of 12 respectively), and a reduction in complications (9 of 12 versus 4 of 12), length of critical care stay (4 (range 2-20) days in group 1 versus 3 (1-5) days in group 3) and length of hospital stay (17 (12-30) to 7 (6-37) days respectively). Patients not on the pathway but who had surgery during the same interval experienced small but non-significant improvements in length of critical care and hospital stay, and in first-day mobilization. CONCLUSION: The study demonstrated improvement in short-term outcomes after oesophagectomy following the adoption of an established multidisciplinary standardized postoperative pathway.

Systematic review and pooled analysis assessing the association between elderly age and outcome following surgical resection of esophageal malignancy.

The incidence of esophageal malignancy continues to increase worldwide. At the same time, average life expectancy levels continue to climb, ensuring that more patients will present in their 70s, 80s, and 90s. The aim of this pooled analysis is to compare short- and long-term outcomes for elderly and younger patients undergoing esophagectomy for malignancy. Studies comparing the outcomes of esophagectomy for malignancy in elderly and young cohorts of patients were included. The minimum threshold age used to define the elderly cohort was 70 years. Primary outcomes were in-hospital mortality, overall and cancer-related 5-year survival. Secondary outcomes were the length of hospital stay, the incidence of anastomotic leak, conduit ischemia, cardiac and pulmonary complications, and the use of neoadjuvant therapy. Twenty-five publications comprising 9531 and 2573 operations on younger and elderly cohorts of patients respectively were analyzed. Elderly patients were less likely to receive neoadjuvant therapy (14.6% vs. 29.47%; pooled odds ratio [POR]= 0.48; 95% confidence interval [C.I.]= 0.35-0.65; P < 0.05). Esophagectomy in elderly patients was associated with increased in-hospital mortality (7.83% vs. 4.21%; POR = 1.87; 95% C.I. = 1.54-2.26; P < 0.05), as well as increased pulmonary (21.77% vs. 19.49%) and cardiac (18.7% vs. 13.17%) complications. Subset analysis of studies using an age threshold of 80 years showed an even more significant association between in-hospital mortality and elderly age (pooled odds ratio = 3.19; 95% C.I. = 1.6-6.35; P < 0.05). There were no significant differences between the groups in length of hospital stay, incidence of anastomotic leak, or conduit ischemia. The elderly group showed reduced overall 5-year survival (21.23% vs. 29.01%; pooled odds ratio = 0.73; 95% C.I. = 0.62-0.87; P < 0.05) and reduced cancer-free 5-year survival (34.4% vs. 41.8%; POR = 0.75; 95% C.I. = 0.64-0.89; P < 0.05). Elderly patients are at increased risk of pulmonary and cardiac complications, and perioperative mortality following esophagectomy, and show reduced cancer-related 5-year survival compared with younger patients. These patients represent a high-risk cohort, who requires thorough assessment of medical comorbidity, targeted counseling, and optimized treatment pathways.

Plasmid comparison and molecular analysis of Klebsiella pneumoniae harbouring bla(KPC) from New York City and Toronto.

OBJECTIVES: This study examined Klebsiella pneumoniae clinical isolates and their bla(KPC) plasmids to determine potential relatedness of the isolates and their plasmids harbouring carbapenem resistance mechanisms. METHODS: K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae from New York City (NYC) (n = 19) and Toronto (n = 2) were typed by PFGE and multilocus sequence typing (MLST). bla(KPC)-harbouring plasmids were transformed into Escherichia coli DH10B(TM), restricted using EcoRI and analysed for bla content and replicon (rep) type. Susceptibility profiles for clinical and transformed strains were determined by automated microbroth dilution using CLSI breakpoints. Outer membrane protein (OMP) genes were analysed by sequencing of ompk35 and ompk36. RESULTS: PFGE analysis identified 17 related strains (≥ 80% similarity; 11 KPC-2, 6 KPC-3) where ST258 was the dominant clonal type. All clinical isolates contained both bla(SHV) and bla(TEM-1) and, with the exception of one isolate, were multidrug resistant (MDR). Transformed KPC plasmids (n = 21) carried TEM-1 (n = 18) and were MDR (n = 5). Three plasmid clusters, repFIIA (n = 10), repR (n = 3) and an unknown type (n = 3), were observed. repFllA plasmids were observed from both NYC and Toronto strains. OMP gene analysis revealed premature stop codons in ompk35 and numerous deletions and insertions in ompk36. CONCLUSIONS: The dissemination of bla(KPC) is due both to carriage of similar KPC-harbouring plasmids within genetically distinct K. pneumoniae and to clonal spread of K. pneumoniae with unrelated KPC plasmids.

Impact of endoscopic assessment and treatment on operative and non-operative management of acute oesophageal perforation.

BACKGROUND: Surgeons have not typically utilized an endoscopic approach for diagnosis and management of acute oesophageal perforation, mainly due to fears of increased mediastinal contamination. This study assessed the evolution of endoscopic approaches and their effect on outcomes over time in acute oesophageal perforation. METHODS: All patients with documented acute oesophageal perforation between 1990 and 2009 were enrolled prospectively in an Institutional Review Board-approved database. RESULTS: Of 81 patients who presented during the study period, 52 had upper gastrointestinal endoscopy for diagnosis alone (12 patients; 23 per cent) or as a component of acute management (40 patients; 77 per cent). Use of endoscopy increased from four of 13 patients in the first 5 years of the study to 20 of 24 patients in the final 5 years. Endoscopy was used in conjunction with surgery in 28 patients, of whom 21 underwent primary repair, three had resection, and one a diversion; 12 patients in this group had hybrid operations (combination of surgical and endoscopic management). Primary endoscopic treatment was used in 15 patients (29 per cent), most commonly involving stent placement (7). Of those having endoscopy, complication rates improved (from 3 of 4 to 8 of 20 patients), as did mean length of stay (from 21·8 to 13·4 days) between the initial and final 5 years of the study. There were two deaths (4 per cent). Of 21 patients who had both endoscopic assessment and management in the operating room, endoscopy identified additional pathology in ten, leading to a change in management plan in five patients. CONCLUSION: Endoscopy is a safe and important component of the management of acute oesophageal perforation. It provides additional information that modifies treatment, and its wider use should result in improved outcomes.

Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis.

Microbial pathogens must evade the human immune system to survive, disseminate and cause disease. By proteome analysis of the bacterium Group A Streptococcus (GAS), we identified a secreted protein with homology to the alpha-subunit of Mac-1, a leukocyte beta2 integrin required for innate immunity to invading microbes. The GAS Mac-1-like protein (Mac) was secreted by most pathogenic strains, produced in log-phase and controlled by the covR-covS two-component gene regulatory system, which also regulates transcription of other GAS virulence factors. Patients with GAS infection had titers of antibody specific to Mac that correlated with the course of disease, demonstrating that Mac was produced in vivo. Mac bound to CD16 (FcgammaRIIIB) on the surface of human polymorphonuclear leukocytes and inhibited opsonophagocytosis and production of reactive oxygen species, which resulted in significantly decreased pathogen killing. Thus, by mimicking a host-cell receptor required for an innate immune response, the GAS Mac protein inhibits professional phagocyte function by a novel strategy that enhances pathogen survival, establishment of infection and dissemination.

Rapid selection of complement-inhibiting protein variants in group A Streptococcus epidemic waves.

Serotype M1 group A Streptococcus strains cause epidemic waves of human infections long thought to be mono- or pauciclonal. The gene encoding an extracellular group A Streptococcus protein (streptococcal inhibitor of complement) that inhibits human complement was sequenced in 1,132 M1 strains recovered from population-based surveillance of infections in Canada, Finland and the United States. Epidemic waves are composed of strains expressing a remarkably heterogeneous array of variants of streptococcal inhibitor of complement that arise very rapidly by natural selection on mucosal surfaces. Thus, our results enhance the understanding of pathogen population dynamics in epidemic waves and infectious disease reemergence.

Evidence for a clonal origin of methicillin resistance in Staphylococcus aureus.

Soon after methicillin was introduced into clinical practice in the early 1960s, resistant strains of Staphylococcus aureus (MRSA) appeared, bearing a newly acquired resistance gene, mecA, that encodes a penicillin binding protein, PBP2a. MRSA have spread throughout the world, and an investigation of the clonality of 472 isolates by DNA hybridization was performed. All 472 isolates could be divided into six temporally ordered mecA hybridization patterns, and three of these were subdivided by the chromomosomal transposon Tn554. Each Tn554 pattern occurred in association with one and only one mecA pattern, suggesting that mecA divergence preceded the acquisition of Tn554 in all cases and therefore that mecA may have been acquired just once by S. aureus.

Characterization of Clostridium difficile strains isolated from patients in Ontario, Canada, from 2004 to 2006.

Clostridium difficile is the bacterium most commonly surmised to cause antimicrobial- and hospital-associated diarrhea in developed countries worldwide, and such infections are thought to be increasing in frequency and severity. A laboratory-based study was carried out to characterize C. difficile strains isolated from persons in Ontario, Canada, during 2004 to 2006 according to toxin type (enterotoxin A, cytotoxin B, and binary toxin [CDT]), tcdC gene characterization, ribotyping, pulsed-field gel electrophoresis, and toxinotyping. Clostridium difficile was isolated from 1,080/1,152 (94%) samples from 21 diagnostic laboratories. Isolates with toxin profiles A(+) B(+) CDT(-), A(+) B(+) CDT(+), A(-) B(+) CDT(-), and A(-) B(+) CDT(+) accounted for 63%, 34%, 2.4%, and 0.6% of isolates, respectively. Alterations in tcdC were detected in six different ribotypes, including ribotype 027. A total of 39 different ribotypes were identified, with ribotype 027/North American pulsotype 1 (NAP1), an internationally recognized outbreak strain associated with severe disease, being the second most common ribotype (19% of isolates). Transient resistance to metronidazole was identified in 19 (1.8%) isolates. While a large number of ribotypes were found, a few predominated across the province. The high prevalence and wide distribution of ribotype 027/NAP1 are disconcerting in view of the severity of disease associated with it.

Genotypic investigation of Clostridium difficile in Prince Edward Island.

Clostridium difficile is an important cause of disease in Canada; however, little information is available about the disease in the Maritime provinces. The objective of the present study was to characterize C difficile isolates obtained from people hospitalized with C difficile infection in Prince Edward Island. One hundred twenty-six C difficile ELISA toxin-positive stool samples were obtained and cultured using an enrichment protocol. C difficile was isolated from 105 of 126 (83%) samples. Twenty-two different ribotypes were identified. The most common ribotype, ribotype W, was a North American pulsotype 2 (NAP2), toxinotype 0 strain, which represented 18% of isolates. The next most common ribotype was a NAP1, toxinotype III strain, which accounted for 11% of isolates. Ribotype 027/NAP1 only accounted for five (4.7%) isolates. Forty-five per cent of isolates possessed genes encoding production of binary toxin. Three different ribotypes, all NAP1, toxinotype III strains, had a frameshift mutation in the tcdC gene (Delta117), while one isolate (ribotype 078, NAP4, toxinotype V) had a truncating mutation (C184T) in the tcdC gene.

Antipneumococcal activity of ertapenem compared with gatifloxacin in a temperature-sensitive murine model of acute pneumonia.

Fluoroquinolone-resistance among pneumococci is low; however the number of isolates with a single ParC mutation has increased. Consequently, more potent agents are needed to minimize resistance selection. We investigated the efficacy of ertapenem versus gatifloxacin in a temperature-sensitive mouse model of pneumonia caused by a wildtype Streptococcus pneumoniae strain (A66) and an isogenic mutant with a ParC mutation (R222). Treatment started at 24 h and lasted for 5 days. Temperature was used to assess disease progression before and during treatment. Of mice infected with either strain and treated at an early stage of infection, 79-94% of those given ertapenem survived compared with 56-61% given gatifloxacin. If treated at a later stage, the results were similar for ertapenem (71-84%) but were considerably lower for gatifloxacin (17-33%). Ertapenem was as bactericidal as gatifloxacin against A66 (94-100% vs 92-100%) but was superior to gatifloxacin against R222 (95-100% vs 50-77%). Ertapenem is a promising new treatment for patients with pneumococcal pneumonia, including those at risk of infection with a fluoroquinolone-resistant strain.

Macrolide resistance in bacteremic pneumococcal disease: implications for patient management.

BACKGROUND: Despite pneumococcal antibiotic resistance rates in excess of 25%, macrolides remain first-line agents for the treatment of community-acquired pneumonia. METHODS: Prospective, population-based surveillance was conducted to identify cases of pneumococcal bacteremia in Toronto and Peel, Canada, between 2000 and 2004. "Macrolide failures" were defined as cases of bacteremia occurring during outpatient treatment with macrolide antibiotics or within 2 days after treatment. Macrolide susceptibility was determined according to Clinical Laboratory Standards Institute guidelines; common macrolide resistance mechanisms were determined by genotyping. RESULTS: During the 5 years of surveillance, there were 1696 episodes of pneumococcal bacteremia (8.5 cases/100,000 population/year), of which 60 (3.5%) were failures of outpatient macrolide therapy. Resistant isolates were more common among cases of bacteremia after failure of macrolide therapy (37 [64%] of 58 cases) than among cases of bacteremia after failure of nonmacrolide antibiotics (16 [22%] of 74 cases; P<.001) or cases of bacteremia that occurred without prior antibiotic therapy (193 [12%] of 1569 cases; P<.001). Macrolide failures were significantly more common among cases of pneumococcal bacteremia with isolates exhibiting an erythromycin MIC of 1 microg/mL than among isolates exhibiting MICs < or = 0.25 microg/mL (3 [38%] of 8 cases vs. 21 [1.5%] of 1394 cases of bacteremia; P<.001). Increases in the MIC to 1 microg/mL were not associated with further increases in the likelihood of macrolide failure. Low-level resistance conferred by mefA and high-level resistance conferred by ermB were equally overrepresented among macrolide failures. CONCLUSIONS: Macrolide resistance contributes to an increased risk of macrolide failure, irrespective of the underlying resistance mechanism or of the degree of elevation in erythromycin MIC.