IGNITE4: Results of a Phase 3, Randomized, Multicenter, Prospective Trial of Eravacycline vs Meropenem in the Treatment of Complicated Intraabdominal Infections.

BACKGROUND: Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum ß-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae. METHODS: IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4-14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25-31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated. RESULTS: Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, -0.5%; 95% confidence interval [CI], -6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, -4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI -2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively. CONCLUSIONS: Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens. CLINICAL TRIALS REGISTRATION: NCT01844856.

Effectiveness of 80% vs 30-35% fraction of inspired oxygen in patients undergoing surgery: an updated systematic review and meta-analysis.

BACKGROUND: In 2016, the World Health Organization (WHO) strongly recommended the use of a high fraction of inspired oxygen (FiO2) in adult patients undergoing general anaesthesia to reduce the risk of surgical site infection (SSI). Since then, further trials have been published, trials included previously have come under scrutiny, and one article was retracted. We updated the systematic review on which the recommendation was based. METHODS: We performed a systematic literature search from January 1990 to April 2018 for RCTs comparing the effect of high (80%) vs standard (30-35%) FiO2 on the incidence of SSI. Studies retracted or under investigation were excluded. A random effects model was used for meta-analyses; the sources of heterogeneity were explored using meta-regression. RESULTS: Of 21 RCTs included, six were newly identified since the publication of the WHO guideline review; 17 could be included in the final analyses. Overall, no evidence for a reduction of SSI after the use of high FiO2 was found [relative risk (RR): 0.89; 95% confidence interval (CI): 0.73-1.07]. There was evidence that high FiO2 was beneficial in intubated patients [RR: 0.80 (95% CI: 0.64-0.99)], but not in non-intubated patients [RR: 1.20 (95% CI: 0.91-1.58); test of interaction; P=0.048]. CONCLUSIONS: The WHO updated analyses did not show definite beneficial effect of the use of high perioperative FiO2, overall, but there was evidence of effect of reducing the SSI risk in surgical patients under general anaesthesia with tracheal intubation. However, the evidence for this beneficial effect has become weaker and the strength of the recommendation needs to be reconsidered.

Safety of 80% vs 30-35% fraction of inspired oxygen in patients undergoing surgery: a systematic review and meta-analysis.

BACKGROUND: Evidence-based guidelines from the World Health Organization (WHO) have recommended a high (80%) fraction of inspired oxygen (FiO2) to reduce surgical site infection in adult surgical patients undergoing general anaesthesia with tracheal intubation. However, there is ongoing debate over the safety of high FiO2. We performed a systematic review to define the relative risk of clinically relevant adverse events (AE) associated with high FiO2. METHODS: We reviewed potentially relevant articles from the WHO review supporting the recommendation, including an updated (July 2018) search of EMBASE and PubMed for randomised and non-randomised controlled studies reporting AE in surgical patients receiving 80% FiO2 compared with 30-35% FiO2. We assessed study quality and performed meta-analyses of risk ratios (RR) comparing 80% FiO2 against 30-35% for major complications, mortality, and intensive care admission. RESULTS: We included 17 moderate-good quality trials and two non-randomised studies with serious-critical risk of bias. No evidence of harm with high FiO2 was found for major AE in the meta-analysis of randomised trials: atelectasis RR 0.91 [95% confidence interval (CI) 0.59-1.42); cardiovascular events RR 0.90 (95% CI 0.32-2.54); intensive care admission RR 0.93 (95% CI 0.7-1.12); and death during the trial RR 0.49 (95% CI 0.17-1.37). One non-randomised study reported that high FiO2 was associated with major respiratory AE [RR 1.99 (95% CI 1.72-2.31)]. CONCLUSIONS: No definite signal of harm with 80% FiO2 in adult surgical patients undergoing general anaesthesia was demonstrated and there is little evidence on safety-related issues to discourage its use in this population.

Antimicrobial Stewardship in Surgery: Challenges and Opportunities.

Antibiotic stewardship programs have been playing an increasingly important role in patient care and hospital policies. The role of these programs in surgical care presents several unique challenges and opportunities, most notably in the perioperative setting. Controversy remains regarding optimal antibiotic choice, dosage, and length of prophylaxis. Here, we review current best practices and suggest areas for further research specific to antibiotic stewardship in surgical care.

Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI).

BACKGROUND: Increasing antimicrobial resistance among pathogens causing complicated intra-abdominal infections (cIAIs) supports the development of new antimicrobials. Ceftolozane/tazobactam, a novel antimicrobial therapy, is active against multidrug-resistant Pseudomonas aeruginosa and most extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. METHODS: ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections) was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) every 8 hours or meropenem (1 g) every 8 hours intravenously for 4-14 days. The prospectively defined objectives were to demonstrate statistical noninferiority in clinical cure rates at the test-of-cure visit (24-32 days from start of therapy) in the microbiological intent-to-treat (primary) and microbiologically evaluable (secondary) populations using a noninferiority margin of 10%. Microbiological outcomes and safety were also evaluated. RESULTS: Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in the primary (83.0% [323/389] vs 87.3% [364/417]; weighted difference, -4.2%; 95% confidence interval [CI], -8.91 to .54) and secondary (94.2% [259/275] vs 94.7% [304/321]; weighted difference, -1.0%; 95% CI, -4.52 to 2.59) endpoints, meeting the prespecified noninferiority margin. In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 95.8% (23/24) and 88.5% (23/26) in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively, and 100% (13/13) and 72.7% (8/11) in patients with CTX-M-14/15 ESBLs. The frequency of adverse events (AEs) was similar in both treatment groups (44.0% vs 42.7%); the most common AEs in either group were nausea and diarrhea. CONCLUSIONS: Treatment with ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in adult patients with cIAI, including infections caused by multidrug-resistant pathogens. CLINICAL TRIALS REGISTRATION: NCT01445665 and NCT01445678.

Multicenter, double-blind, randomized, phase II trial to assess the safety and efficacy of ceftolozane-tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections.

Ceftolozane-tazobactam (TOL-TAZ) is a novel antibacterial with activity against Pseudomonas aeruginosa and other common Gram-negative pathogens, including extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae, that are associated with complicated intra-abdominal infections (cIAIs). This prospective, double-blind, randomized, multicenter, phase II trial assessed patient clinical and microbiological responses to and the safety of TOL-TAZ plus metronidazole compared with those of meropenem. Hospitalized adults with cIAIs that required surgical intervention were randomized (2:1) to receive intravenous (i.v.) TOL-TAZ (1.5 g [containing 1,000 mg TOL and 500 mg TAZ] every 8 h [q8h]) with or without i.v. metronidazole (500 mg q8h) or i.v. meropenem (1 g q8h) for 4 to 7 days. The primary endpoint was the clinical response at the test-of-cure visit in the microbiologically modified intent-to-treat (mMITT) and microbiologically evaluable (ME) populations. Secondary measures included the patients' microbiological response and safety. In total, 82 patients received TOL-TAZ (90.2% with metronidazole), and 39 received meropenem. For the mMITT population, clinical cure was seen in 83.6% of the patients (51/61; 95% confidence interval [CI], 71.9 to 91.8) who received TOL-TAZ and 96.0% of the patients (24/25; 95% CI, 79.6 to 99.9) who received meropenem (difference, -12.4%; 95% CI, -34.9% to 11.1%); in the ME population, clinical cure was seen in 88.7% and 95.8% of the patients (difference, -7.1%; 95% CI, -30.7% to 16.9%) who received TOL-TAZ and meropenem, respectively. TOL-TAZ demonstrated microbiological success against Escherichia coli (89.5%), Klebsiella pneumoniae (100%), and P. aeruginosa (100%). The adverse event rates were similar in the groups (50.0% with TOL-TAZ and 48.8% with meropenem). TOL-TAZ in combination with metronidazole was well tolerated and resulted in clinical and microbiological success rates supportive of further clinical development in patients with cIAIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01147640.).

Phase 2, randomized, double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community-acquired complicated intra-abdominal infections.

Eravacycline is a novel fluorocycline, highly active against Gram-positive and Gram-negative pathogens in vitro, including those with tetracycline and multidrug resistance. This phase 2, randomized, double-blind study was conducted to evaluate the efficacy and safety of two dose regimens of eravacycline compared with ertapenem in adult hospitalized patients with complicated intra-abdominal infections (cIAIs). Patients with confirmed cIAI requiring surgical or percutaneous intervention and antibacterial therapy were randomized (2:2:1) to receive eravacycline at 1.5 mg/kg of body weight every 24 h (q24h), eravacycline at 1.0 mg/kg every 12 h (q12h), or ertapenem at 1 g (q24h) for a minimum of 4 days and a maximum of 14 days. The primary efficacy endpoint was the clinical response in microbiologically evaluable (ME) patients at the test-of-cure (TOC) visit 10 to 14 days after the last dose of study drug therapy. Overall, 53 patients received eravacycline at 1.5 mg/kg q24h, 56 received eravacycline at 1.0 mg/kg q12h, and 30 received ertapenem. For the ME population, the clinical success rate at the TOC visit was 92.9% (39/42) in the group receiving eravacycline at 1.5 mg/kg q24h, 100% (41/41) in the group receiving eravacycline at 1.0 mg/kg q12h, and 92.3% (24/26) in the ertapenem group. The incidences of treatment-emergent adverse events were 35.8%, 28.6%, and 26.7%, respectively. Incidence rates of nausea and vomiting were low in both eravacycline groups. Both dose regimens of eravacycline were as efficacious as the comparator, ertapenem, in patients with cIAI and were well tolerated. These results support the continued development of eravacycline for the treatment of serious infections, including those caused by drug-resistant Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01265784.).

Source control review in clinical trials of anti-infective agents in complicated intra-abdominal infections.

In clinical trials of complicated intra-abdominal infections, assessment of adequacy of the initial surgical approach to the management of the infection is of considerable importance in determining outcome. Antibiotic therapy would not be expected to adequately treat the infection if the surgical procedure was inadequate with respect to source control. Inclusion of such cases in an efficacy analysis of a particular therapeutic antibiotic may confound the results. We analyzed the source control review process used in double-blind clinical trials of antibiotics in complicated intra-abdominal infections identified through systematic review. We searched MEDLINE (PubMed) and ClinicalTrials.gov databases to identify relevant articles reporting results from double-blind clinical trials that used a source control review process. Eight prospective, randomized, double-blind, multicenter, clinical trials of 5 anti-infective agents in complicated intra-abdominal infections used a source control review process. We provide recommendations for an independent, adjudicated source control review process applicable to future clinical trials.

Surgical site infections among high-risk patients in clean-contaminated head and neck reconstructive surgery: concordance with preoperative oral flora.

BACKGROUND: Salivary contamination of surgical wounds in clean-contaminated head and neck surgery with free flap reconstruction remains a major cause of infection and leads to significant morbidity. This study investigates the correlation between intraoral flora and surgical site infections (SSIs) among high-risk head and neck cancer patients undergoing resection and free flap reconstruction. METHODS: One hundred twenty-nine patients were identified as being at high risk for infective complications based on cancer stage, tumor size, comorbid factors, and extent of reconstruction. All patients had intraoral swab cultures before surgery. Patients with culture-confirmed SSI after surgery were chosen for analysis, using the κ index and its 95% confidence interval for concordance analysis. All patients received clindamycin and gentamicin for antibiotic prophylaxis for 5 days. Antibiotic susceptibility testing of all isolates was obtained and analyzed. RESULTS: Thirty-seven patients experienced SSI, or an infection rate of 28.3%, occurring at a mean of 9.3 postoperative days. The overall concordance between oral flora and SSI was fair to moderate (κ index of 0.25), but detailed analysis shows a higher concordance for known and opportunistic pathogens, such as Pseudomonas aeruginosa and Enterococcus faecalis, compared to typical oral commensals. Antibiotic susceptibility tests show rapid and significant increases in resistance to clindamycin, indicating a need for a more effective alternative. CONCLUSIONS: Predicting pathogens in SSI using preoperative oral swabs did not demonstrate a good concordance in general for patients undergoing clean-contaminated head and neck surgery, although concordance for certain pathogenic species seem to be higher than for typical intraoral commensals. The rapid development of resistance to clindamycin precludes its use as a prophylactic agent.

Vancomycin for surgical prophylaxis?

The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has resulted in a reevaluation of the role of vancomycin for surgical prophylaxis. Two systematic reviews of randomized control studies have concluded that cephalosporins are as effective as vancomycin for the prevention of surgical site infections (SSIs). However, most of these studies were conducted more than 10 years ago and cannot be generalized to the current rates of MRSA. Several time-series analyses have recently evaluated the effectiveness of vancomycin for surgical prophylaxis in institutions with a high prevalence of MRSA. Decision analysis models have also been used to estimate thresholds of MRSA prevalence for which vancomycin would minimize the incidence and cost of SSIs. Combination therapy and the emergence of resistant pathogens following vancomycin prophylaxis are reviewed. Vancomycin is not recommended for routine use in surgical prophylaxis but may be considered as a component of a MRSA prevention bundle for SSIs in selective circumstances.

Clinical efficacy and correlation of clinical outcomes with in vitro susceptibility for anaerobic bacteria in patients with complicated intra-abdominal infections treated with moxifloxacin.

BACKGROUND: Appropriate antimicrobial therapy results in improved clinical outcomes in complicated intra-abdominal infections (cIAIs). Recent in vitro studies have reported increasing moxifloxacin resistance of Bacteroides species, thereby cautioning empiric use in infections with these organisms. METHODS: This pooled analysis of 4 randomized clinical trials (2000-2010) evaluated the comparative efficacy of moxifloxacin in cIAIs, including infection with anaerobic organisms. The intent-to-treat population included 1209 patients who received moxifloxacin (745 microbiologically valid cases) and 1193 patients who received comparator agents (741 microbiologically valid cases). RESULTS: Overall clinical success rates in the per-protocol population were 85.6% (817 of 955 patients) for moxifloxacin and 87.8% (860 of 979 patients) for comparators. Of 642 pretherapy anaerobes from moxifloxacin-treated patients, 561 (87.4%) were susceptible at ≤2 mg/L, 34 (5.3%) were intermediate at 4 mg/L, and 47 (7.3%) were resistant at ≥8 mg/L. Moxifloxacin achieved similar clinical success rates against all anaerobes including those isolated from patients infected with Bacteroides fragilis (158 [82.7%] of 191 patients), Bacteroides thetaiotaomicron (74 [82.2%] of 90 patients) and Clostridium species (37 [80.4%] of 46 patients). The overall clinical success rate for all anaerobes was 82.3%. For all anaerobes combined, the clinical success rate was 83.1% (466 of 561 patients) for a minimum inhibitory concentration (MIC) of ≤2 mg/L, 91.2% (31 of 34 patients) for an MIC of 4 mg/L, 82.4% (14 of 17 patients) for an MIC of 8 mg/L, 83.3% (5 of 6 patients) for an MIC of 16 mg/L, and 66.7% (16 of 24 patients) for an MIC of ≥32 mg/L. CONCLUSIONS: Moxifloxacin demonstrated clinical success for intra-abdominal infections caused by both aerobic and anaerobic isolates. More than 87% of baseline anaerobic isolates from intra-abdominal infections were susceptible to moxifloxacin, and efficacy was maintained beyond the current susceptibility breakpoint MIC of ≤2 mg/L against major anaerobes.

Updated recommendations for control of surgical site infections.

OBJECTIVE: The objective of this study is to provide updated guidelines for the prevention of surgical wound infections based upon review and interpretation of the current and past literature. BACKGROUND: The development and treatment of surgical wound infections has always been a limiting factor to the success of surgical treatment. Although continuous improvements have been made, surgical site infections continue to occur at an unacceptable rate, annually costing billions of dollars in economic loss caused by associated morbidity and mortality. METHODS: The Centers for Disease Control (CDC) provided extensive recommendations for the control of surgical infections in 1999. Review of the current literature with interpretation of the findings has been done to update the recommendations. RESULTS: New and sometimes conflicting studies indicate that coordination and application of techniques and procedures to decrease wound infections will be highly successful, even in patients with very high risks. CONCLUSIONS: This review suggests that uniform adherence to the proposed guidelines for the prevention of surgical infections could reduce wound infections significantly; namely to a target of less than 0.5% in clean wounds, less than 1% in clean contaminated wounds and less than 2% in highly contaminated wounds and decrease related costs to less than one-half of the current amount.

Prevention of infections associated with combat-related thoracic and abdominal cavity injuries.

Trauma-associated injuries of the thorax and abdomen account for the majority of combat trauma-associated deaths, and infectious complications are common in those who survive the initial injury. This review focuses on the initial surgical and medical management of torso injuries intended to diminish the occurrence of infection. The evidence for recommendations is drawn from published military and civilian data in case reports, clinical trials, meta-analyses, and previously published guidelines, in the interval since publication of the 2008 guidelines. The emphasis of these recommendations is on actions that can be taken in the forward-deployed setting within hours to days of injury. This evidence-based medicine review was produced to support the Guidelines for the Prevention of Infections Associated With Combat-Related Injuries: 2011 Update contained in this supplement of Journal of Trauma.

Executive summary: Guidelines for the prevention of infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of America and the Surgical Infection Society.

Despite advances in resuscitation and surgical management of combat wounds, infection remains a concerning and potentially preventable complication of combat-related injuries. Interventions currently used to prevent these infections have not been either clearly defined or subjected to rigorous clinical trials. Current infection prevention measures and wound management practices are derived from retrospective review of wartime experiences, from civilian trauma data, and from in vitro and animal data. This update to the guidelines published in 2008 incorporates evidence that has become available since 2007. These guidelines focus on care provided within hours to days of injury, chiefly within the combat zone, to those combat-injured patients with open wounds or burns. New in this update are a consolidation of antimicrobial agent recommendations to a backbone of high-dose cefazolin with or without metronidazole for most postinjury indications and recommendations for redosing of antimicrobial agents, for use of negative pressure wound therapy, and for oxygen supplementation in flight.

Guidelines for the prevention of infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of America and the Surgical Infection Society.

Despite advances in resuscitation and surgical management of combat wounds, infection remains a concerning and potentially preventable complication of combat-related injuries. Interventions currently used to prevent these infections have not been either clearly defined or subjected to rigorous clinical trials. Current infection prevention measures and wound management practices are derived from retrospective review of wartime experiences, from civilian trauma data, and from in vitro and animal data. This update to the guidelines published in 2008 incorporates evidence that has become available since 2007. These guidelines focus on care provided within hours to days of injury, chiefly within the combat zone, to those combat-injured patients with open wounds or burns. New in this update are a consolidation of antimicrobial agent recommendations to a backbone of high-dose cefazolin with or without metronidazole for most postinjury indications, and recommendations for redosing of antimicrobial agents, for use of negative pressure wound therapy, and for oxygen supplementation in flight.