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.

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.

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.

Meta-analysis of trials evaluating parenteral antimicrobial therapy for skin and soft tissue infections.

BACKGROUND: Many trials have been carried out to determine the effectiveness of antimicrobial agents in treating skin and soft tissue infections. The results of these studies are often utilized to make determinations about the use of these antimicrobials against other types of infections. Despite the importance of these trials in determining clinical care, we hypothesized that many of these studies failed to include a variety of infections of significant enough severity to effectively draw objective conclusions about antimicrobial efficacy. METHODS: We conducted a modified PubMed search to identify studies of antimicrobial agents in treating soft tissue infections that were published from 1998 through 2008. We then evaluated these trials for specific recommended study criteria, which were based on published US Food and Drug Administration guidelines for the conduct of trials of antimicrobials for soft tissue infection. RESULTS: Seventeen studies were identified for inclusion in the trial. Upon review, only 30% of trials required both local and systemic signs of infection for inclusion in the trial. One trial stratified results on the basis of operative intervention, less than half reported patient comorbidities, and only 53% provided a specific definition for "cure." CONCLUSIONS: Our meta-analysis of current trials evaluating antimicrobial therapy for skin and soft tissue infections revealed substantial shortcomings in the design of most of these trials. These data provide evidence for the importance of designing specialist panels to objectively evaluate studies and photographs of included infections to ensure that conclusions drawn from these trials concerning clinical practice are justified.

Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America.

Evidence-based guidelines for managing patients with intra-abdominal infection were prepared by an Expert Panel of the Surgical Infection Society and the Infectious Diseases Society of America. These updated guidelines replace those previously published in 2002 and 2003. The guidelines are intended for treating patients who either have these infections or may be at risk for them. New information, based on publications from the period 2003-2008, is incorporated into this guideline document. The panel has also added recommendations for managing intra-abdominal infection in children, particularly where such management differs from that of adults; for appendicitis in patients of all ages; and for necrotizing enterocolitis in neonates.

Divergent adaptive and innate immunological responses are observed in humans following blunt trauma.

BACKGROUND: The immune response to trauma has traditionally been modeled to consist of the systemic inflammatory response syndrome (SIRS) followed by the compensatory anti-inflammatory response syndrome (CARS). We investigated these responses in a homogenous cohort of male, severe blunt trauma patients admitted to a University Hospital surgical intensive care unit (SICU). After obtaining consent, peripheral blood was drawn up to 96 hours following injury. The enumeration and functionality of both myeloid and lymphocyte cell populations were determined. RESULTS: Neutrophil numbers were observed to be elevated in trauma patients as compared to healthy controls. Further, neutrophils isolated from trauma patients had increased raft formation and phospho-Akt. Consistent with this, the neutrophils had increased oxidative burst compared to healthy controls. In direct contrast, blood from trauma patients contained decreased naïve T cell numbers. Upon activation with a T cell specific mitogen, trauma patient T cells produced less IFN-gamma as compared to those from healthy controls. Consistent with these results, upon activation, trauma patient T cells were observed to have decreased T cell receptor mediated signaling. CONCLUSIONS: These results suggest that following trauma, there are concurrent and divergent immunological responses. These consist of a hyper-inflammatory response by the innate arm of the immune system concurrent with a hypo-inflammatory response by the adaptive arm.

CAGS and ACS evidence based reviews in surgery. 35: Efficacy and safety of low-dose hydrocortisone therapy in the treatment of septic shock.

OBJECTIVE: To evaluate the efficacy and safety of low-dose hydrocortisone therapy in patients with septic shock. DESIGN: Multicentre, randomized, double-blind, placebo-controlled trial. SETTING: Nine centres (including 52 intensive care units) in Europe and the Middle East. PATIENTS: Patients with clinical evidence of infection, evidence of systemic response to infection and onset of shock within the previous 72 hours (defined by systolic blood pressure < 90 mm Hg despite adequate fluid replacement or a need for vasopressors for at least 1 hour) and hypoperfusion or organ dysfunction attributable to sepsis. INTERVENTION: INTERVENTION group (n = 251) was randomly assigned to receive 50 mg of hydrocortisone intravenously, and the control group (n = 248) was randomly assigned to receive placebo every 6 hours for 5 days; the dose was tapered during a 6-day period. MAIN OUTCOME MEASURE: Death at 28 days in patients who did not have a response to corticotrophin. RESULTS: In all, 233 (46.7%) patients did not have a response to corticotrophin (125 in the treatment group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the 2 groups who did not have a response to corticotropin (39.2% in the treatment group and 36.1% in the placebo group, p = 0.69) or between those who had a response to corticotropin (28.8% in the treatment group and 28.7% in the placebo group, p = 1.00). At 28 days, 86 of 251 (34.3%) patients in the treatment group and 78 of 248 (31.5%) in the placebo group had died (p = 0.51). In the treatment group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock. CONCLUSION: Hydrocortisone cannot be recommended as general adjuvant therapy for septic shock (vasopressor responsive), nor can corticotrophin testing be recommended to determine which patients should receive hydrocortisone therapy.

Effect of postoperative continuation of antibiotic prophylaxis on the incidence of surgical site infection: a systematic review and meta-analysis.

BACKGROUND: Antibiotic prophylaxis is frequently continued for 1 day or more after surgery to prevent surgical site infection. Continuing antibiotic prophylaxis after an operation might have no advantage compared with its immediate discontinuation, and it unnecessarily exposes patients to risks associated with antibiotic use. In 2016, WHO recommended discontinuation of antibiotic prophylaxis after surgery. We aimed to update the evidence that formed the basis for that recommendation. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, CINAHL, CENTRAL, and WHO regional medical databases for randomised controlled trials (RCTs) on postoperative antibiotic prophylaxis that were published from Jan 1, 1990, to July 24, 2018. RCTs comparing the effect of postoperative continuation versus discontinuation of antibiotic prophylaxis on the incidence of surgical site infection in patients undergoing any surgical procedure with an indication for antibiotic prophylaxis were eligible. The primary outcome was the effect of postoperative surgical antibiotic prophylaxis continuation versus its immediate discontinuation on the occurrence of surgical site infection, with a prespecified subgroup analysis for studies that did and did not adhere to current best practice standards for surgical antibiotic prophylaxis. We calculated summary relative risks (RRs) with corresponding 95% CIs using a random effects model (DerSimonian and Laird). We evaluated heterogeneity with the χ2 test, I2, and τ2, and visually assesed publication bias with a contour-enhanced funnel plot. This study is registered with PROSPERO, CRD42017060829. FINDINGS: We identified 83 relevant RCTs, of which 52 RCTs with 19 273 participants were included in the primary meta-analysis. The pooled RR of surgical site infection with postoperative continuation of antibiotic prophylaxis versus its immediate discontinuation was 0·89 (95% CI 0·79-1·00), with low heterogeneity in effect size between studies (τ2=0·001, χ2 p=0·46, I2=0·7%). Our prespecified subgroup analysis showed a significant association between the effect estimate and adherence to best practice standards of surgical antibiotic prophylaxis: the RR of surgical site infection was reduced with continued antibiotic prophylaxis after surgery compared with its immediate discontinuation in trials that did not meet best practice standards (0·79 [95% CI 0·67-0·94]) but not in trials that did (1·04 [0·85-1·27]; p=0·048). Whether studies adhered to best practice standards explained all variance in the pooled estimate from the primary meta-analysis. INTERPRETATION: Overall, we identified no conclusive evidence for a benefit of postoperative continuation of antibiotic prophylaxis over its discontinuation. When best practice standards were followed, postoperative continuation of antibiotic prophylaxis did not yield any additional benefit in reducing the incidence of surgical site infection. These findings support WHO recommendations against this practice. FUNDING: None.