A combination of C-reactive protein and quick sequential organ failure assessment (qSOFA) score has better prognostic accuracy than qSOFA alone in patients with complicated intra-abdominal infections.

INTRODUCTION: Complicated intra-abdominal infections (cIAIs) remain a serious challenge because of their unacceptably high mortality rates. Among different prognostic scoring systems quick-sequential organ failure assessment (qSOFA) score is the most recent. However, as mortality predictor in surgical patients, qSOFA showed lack of sensitivity. The aim of this study was to find prognostic superiority of our new qSOFA-CRP score in patients with cIAIs. MATERIALS AND METHODS: We retrospectively analyzed 78 patients presented to ED and admitted to Department of Surgical Diseases between January 2017 and October 2018 with diagnosis cIAIs. CRP levels, qSOFA score and systemic inflammatory response syndrome (SIRS) were established at admission. We analyzed area under receiver operating characteristics (AUROC) curves of SIRS, qSOFA and qSOFA-CRP and performed a comparison to explore their prognostic values. RESULTS: The identified in-hospital mortality was 25.6%. qSOFA-CRP score showed the best prognostic performance compared to qSOFA alone (AUROC = 0.818 vs. 0.746, p = .0219) and SIRS (AUROC = 0.818 vs. 0.579, p = .0009). The new qSOFA-CRP score ≥2 points showed excellent specificity (91.4%) and the highest sensitivity in comparison to qSOFA ≥2 and SIRS ≥2 (60% vs. 35% vs. 40%) for mortality prediction. CONCLUSIONS: qSOFA-CRP score showed better prognostic value than quick-SOFA alone in patients with cIAIs.

The 2018 Lebanese Society of Infectious Diseases and Clinical Microbiology Guidelines for the use of antimicrobial therapy in complicated intra-abdominal infections in the era of antimicrobial resistance.

BACKGROUND: The Lebanese Society of Infectious Diseases and Clinical Microbiology (LSIDCM) is involved in antimicrobial stewardship. In an attempt at guiding clinicians across Lebanon in regards to the proper use of antimicrobial agents, members of this society are in the process of preparing national guidelines for common infectious diseases, among which are the guidelines for empiric and targeted antimicrobial therapy of complicated intra-abdominal infections (cIAI). The aims of these guidelines are optimizing patient care based on evidence-based literature and local antimicrobial susceptibility data, together with limiting the inappropriate use of antimicrobials thus decreasing the emergence of antimicrobial resistance (AMR) and curtailing on other adverse outcomes. METHODS: Recommendations in these guidelines are adapted from other international guidelines but modeled based on locally derived susceptibility data and on the availability of pharmaceutical and other resources. RESULTS: These guidelines propose antimicrobial therapy of cIAI in adults based on risk factors, site of acquisition of infection, and clinical severity of illness. We recommend using antibiotic therapy targeting third-generation cephalosporin (3GC)-resistant gram negative organisms, with carbapenem sparing as much as possible, for community-acquired infections when the following risk factors exist: prior (within 90 days) exposure to antibiotics, immunocompromised state, recent history of hospitalization or of surgery and invasive procedure all within the preceding 90 days. We also recommend antimicrobial de-escalation strategy after culture results. Prompt and adequate antimicrobial therapy for cIAI reduces morbidity and mortality; however, the duration of therapy should be limited to no more than 4 days when adequate source control is achieved and the patient is clinically stable. The management of acute pancreatitis is conservative, with a role for antibiotic therapy only in specific situations and after microbiological diagnosis. The use of broad-spectrum antimicrobial agents including systemic antifungals and newly approved antibiotics is preferably restricted to infectious diseases specialists. CONCLUSION: These guidelines represent a major step towards initiating a Lebanese national antimicrobial stewardship program. The LSIDCM emphasizes on development of a national AMR surveillance network, in addition to a national antibiogram for cIAI stratified based on the setting (community, hospital, unit-based) that should be frequently updated.

Analysis of patients with diabetes and complicated intra-abdominal infection or complicated urinary tract infection in phase 3 trials of ceftolozane/tazobactam.

BACKGROUND: Diabetes mellitus and hyperglycemia are associated with increased susceptibility to bacterial infections and poor treatment outcomes. This post hoc evaluation of the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) aimed to evaluate baseline characteristics, efficacy, and safety in patients with and without diabetes treated with ceftolozane/tazobactam and comparators. Ceftolozane/tazobactam is an antibacterial with potent activity against Gram-negative pathogens and is approved for the treatment of cIAI (with metronidazole) and cUTI (including pyelonephritis). METHODS: Patients from the phase 3 ASPECT studies with (n = 245) and without (n = 1802) diabetes were compared to evaluate the baseline characteristics, efficacy, and safety of ceftolozane/tazobactam and active comparators. RESULTS: Significantly more patients with than without diabetes were 65 years of age or older; patients with diabetes were also more likely to weigh ≥75 kg at baseline (57.1% vs 44.5%), to have renal impairment (48.5% vs 30.2%), or to have APACHE II scores ≥10 (33.8% vs 17.0%). More patients with diabetes had comorbidities and an increased incidence of complicating factors in both cIAI and cUTI. Clinical cIAI and composite cure cUTI rates across study treatments were lower in patients with than without diabetes (cIAI, 75.4% vs 86.1%, P = 0.0196; cUTI, 62.4% vs 74.7%, P = 0.1299) but were generally similar between the ceftolozane/tazobactam and active comparator treatment groups. However, significantly higher composite cure rates were reported with ceftolozane/tazobactam than with levofloxacin in patients without diabetes with cUTI (79.5% vs 69.9%; P = 0.0048). Significantly higher rates of adverse events observed in patients with diabetes were likely due to comorbidities because treatment-related adverse events were similar between groups. CONCLUSIONS: In this post hoc analysis, patients with diabetes in general were older, heavier, and had a greater number of complicating comorbidities. Patients with diabetes had lower cure rates and a significantly higher frequency of adverse events than patients without diabetes, likely because of the higher rates of medical complications in this subgroup. Ceftolozane/tazobactam was shown to be at least as effective as comparators in treating cUTI and cIAI in this population. TRIAL REGISTRATION: cIAI, NCT01445665 and NCT01445678 (both trials registered prospectively on September 26, 2011); cUTI, NCT01345929 and NCT01345955 (both trials registered prospectively on April 28, 2011).

Re-defining tigecycline therapy.

Tigecycline, the first member of the glycylcyclines, has been approved for complicated skin and soft tissue infections (cSSTIs) and complicated intra-abdominal infections (cIAIs). It has a wide range of activity against Gram-positive and Gram-negative bacteria, including anaerobes. Since its approval, the worldwide clinical use of tigecycline has been heterogeneous, either as a monotherapy or as a part of combination therapy, almost exclusively at the standard dosage, in patients with community-acquired (CA) infections as well as health-care associated (HCA) or nosocomial infections (HA), including infections caused by multidrug-resistant (MDR) bacteria. In recent years, issues and warnings of an increased mortality in these heterogeneous patients treated with tigecycline have been raised by meta-analyses and by regulatory agencies. Re-defining tigecycline therapy is a proposal, based on epidemiological, clinical, microbiological and pharmacological considerations, to distinguish patients who may be treated with monotherapy, according to the official indications and dosages, from those treated with combination treatment, mostly with high dosages in the setting of nosocomial IAIs, possibly caused by MDR bacteria or as a carbapenem-sparing strategy. Whilst available clinical data and guidelines suggest caution with monotherapy in severe infections, experience worldwide indicates that combination treatment with high-dosage tigecycline is increasingly used.

Moxifloxacin-loaded nanoemulsions having tocopheryl succinate as the integral component improves pharmacokinetics and enhances survival in E. coli-induced complicated intra-abdominal infection.

In the present work, a novel nanoemulsion laden with moxifloxacin has been developed for effective management of complicated intra-abdominal infections. Moxifloxacin nanoemulsion fabricated using high pressure homogenization was evaluated for various pharmaceutical parameters, pharmacokinetics (PK) and pharmacodynamics (PD) in rats with E. coli-induced peritonitis and sepsis. The developed nanoemulsion MONe6 (size 168 ± 28 nm and zeta potential (ZP) 24.78 ± 0.45 mV, respectively) was effective for intracellular delivery and sustaining the release of MOX. MONe6 demonstrated improved plasma (AUC(MONe6/MOX) = 2.38-fold) and tissue pharmacokinetics of MOX (AUC(MONe6/MOX) = 2.63 and 1.47 times in lung and liver, respectively). Calculated PK/PD index correlated well with a reduction in bacterial burden in plasma as well as tissues. Enhanced survival on treatment with MONe6 (65.44%) and as compared to the control group (8.22%) was a result of reduction in lipid peroxidation, neutrophil migration, and cytokine levels (TNF-α and IL6) as compared to untreated groups in the rat model of E. coli-induced sepsis. Parenteral nanoemulsions of MOX hold a promising advantage in the therapy of E. coli-induced complicated intra-abdominal infections and is helpful in the prevention of further complications like septic shock and death.

Imipenem/Cilastatin/Relebactam for Complicated Infections: A Real-World Evidence.

(1) Background: Infections caused by multidrug-resistant (MDR) bacteria represent one of the major global public health problems of the 21st century. Beta-lactam antibacterial agents are commonly used to treat infections due to Gram-negative pathogens. New ß-lactam/ß-lactamase inhibitor combinations are urgently needed. Combining relebactam (REL) with imipenem (IMI) and cilastatin (CS) can restore its activity against many imipenem-nonsusceptible Gram-negative pathogens. (2) Methods: we performed a systematic review of the studies reporting on the use of in vivo REAL/IPM/CS. (3) Results: A total of eight studies were included in this review. The primary diagnosis was as follows: complicated urinary tract infection (n = 234), complicated intra-abdominal infections (n = 220), hospital-acquired pneumonia (n = 276), and ventilator-associated pneumonia (n = 157). Patients with normal renal function received REL/IPM/CS (250 mg/500 mg/500 mg). The most frequently reported AEs occurring in patients treated with imipenem/cilastatin plus REL/IPM/CS were nausea (11.5%), diarrhea (9.8%), vomiting (9.8%), and infusion site disorders (4.0%). Treatment outcomes in these high-risk patients receiving REL/IPM/CS were generally favorable. A total of 70.6% of patients treated with REL/IPM/CS reported a favorable clinical response at follow-up. (4) Conclusions: this review indicates that REL/IPM/CS is active against important MDR Gram-negative organisms.

Resistance mechanisms and epidemiology of multiresistant pathogens in Europe and efficacy of tigecycline in observational studies.

OBJECTIVES: Antimicrobial drug resistance is a growing problem in Europe and, even with differences in epidemiology, it is of great concern. The treatment of complicated skin and soft-tissue infections (cSSTIs) and complicated intra-abdominal infections (cIAIs) is hindered further by pathogens that are resistant to methicillin, carbapenems, third-generation cephalosporins and glycopeptides. PATIENTS AND METHODS: An analysis of the microbiological results from five European observational studies (July 2006 to October 2011) evaluating the efficacy of tigecycline (prescribed as monotherapy or in combination with other antibacterials) for the treatment of cSSTI and cIAI is presented. RESULTS: In total, 213 cSSTI and 623 cIAI patients were included; 34.4% and 56.6%, respectively, were critically ill in intensive care units. At baseline, at least one pathogen was isolated in 167 (78.4%) cSSTI and 464 (74.5%) cIAI patients, and 32.9% and 49.1% of infections were polymicrobial. In cSSTI, Staphylococcus aureus and Escherichia coli (52.7% and 18.0%, respectively) were the most frequently isolated pathogens, whereas in cIAI most infections were due to E. coli (41.8%), Enterococcus faecium (40.1%) and Enterococcus faecalis (21.1%). Clinical response was observed in >80% of patients with E. coli in both cIAI and cSSTI. In cSSTI patients, the clinical response rate to S. aureus was 80.8%. For cIAI, 77.4% of E. faecium and 79.5% of E. faecalis patients responded to treatment. CONCLUSIONS: Tigecycline when given alone or in combination with other antibacterials appeared to be efficacious against multiple pathogens, affirming its role in real-life clinical practice as a broad-spectrum antibacterial for the treatment of patients with cSSTI and cIAI, including the critically ill, across Europe.

Prescription behaviours for tigecycline in real-life clinical practice from five European observational studies.

OBJECTIVES: There is limited information on the use of tigecycline in real-life clinical practice. This analysis aims to identify and understand tigecycline prescribing patterns and associated patient outcomes for approved indications. PATIENTS AND METHODS: A pooled analysis of patient-level data collected on the prescription of tigecycline in five European observational studies (July 2006 to October 2011) was conducted. RESULTS: A total of 1782 patients who received tigecycline were included in the analysis. Of these patients, 61.6% were male, the mean age was 63.4 ± 14.7 years, 56.4% were in intensive care units, 80.2% received previous antibiotic treatment and 91% had one or more comorbid conditions. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores at the beginning of treatment were 17.7 ± 7.9 and 7.0 ± 4.0, respectively. The majority of patients (58.3%) received tigecycline for treatment of complicated skin and soft-tissue infections (cSSTIs; n = 254) or complicated intra-abdominal infections (cIAIs; n = 785). Tigecycline was given at the standard dose (100 mg plus 50 mg twice daily) to 89.3% of patients for a mean duration of 11.1 ± 6.4 days. The main reasons for prescribing tigecycline were failure of previous therapy (46.1%), broad-spectrum antibiotic coverage (41.4%) and suspicion of a resistant pathogen (39.3%). Tigecycline was prescribed first-line in 36.3% of patients and as monotherapy in 50.4%. Clinical response rates to treatment with tigecycline alone or in combination were 79.6% (183/230; cSSTIs) and 77.4% (567/733; cIAIs). CONCLUSIONS: Although tigecycline prescription behaviour showed some heterogeneity across the study sites, these results confirm a role for tigecycline in real-life clinical practice for the treatment of complicated infections, including those in critically ill patients, across Europe.

Cost-effectiveness of ceftazidime/avibactam plus metronidazole versus meropenem as first-line empiric therapy for the treatment of complicated intra-abdominal infections: A study based on the in-vitro surveillance data in China.

BACKGROUND: With the increase in drug resistance rates of pathogens isolated from complicated intra-abdominal infections (cIAIs), ceftazidime/avibactam (CAZ-AVI) is increasingly used clinically. However, given the high drug cost and the fact that not yet covered by the health insurance payment, this study evaluated the cost-effectiveness of CAZ-AVI plus metronidazole versus meropenem as a first-line empiric treatment for cIAIs from the perspective of the Chinese healthcare system. METHODS: A decision analytic model with a one-year time horizon was constructed to assess the cost-effectiveness based on the entire disease course. Model inputs were mainly obtained from clinical studies, published literature, and publicly available databases. Primary outcomes were cost, quality-adjusted life years (QALYs), life years (Lys), and incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis and probabilistic sensitivity analysis were also performed. RESULTS: In the base cases, compared to meropenem, CAZ-AVI plus metronidazole had a shorter mean hospital length of stay (-0.77 days per patient) and longer life expectancy (+0.05 LYs and +0.06 QALYs). CAZ-AVI plus metronidazole had an ICER of $25517/QALY, which is well below the threshold of $31509 per QALY in China. The one-way sensitivity analysis showed that the change of the treatment duration of CAZ-AVI plus metronidazole was the parameter that most influenced the results of the ICER. In probabilistic sensitivity analysis, CAZ-AVI plus metronidazole was the optimal strategy in 75% of simulations at $31510/QALY threshold. CONCLUSIONS: CAZ-AVI plus metronidazole could be considered as a cost-effective option for the empiric treatment of patients with cIAIs in China, and this benefit will be more evident when the price of CAZ-AVI decreases by 23.8%.

The efficacy and safety of eravacycline compared with current clinically common antibiotics in the treatment of adults with complicated intra-abdominal infections: A Bayesian network meta-analysis.

Background: Eravacycline is a novel, fully synthetic fluorocycline antibiotic for the treatment of adults with complicated intra-abdominal infections (cIAIs). However, the efficacy and safety of eravacycline compared with current clinically common antibiotics remain unknown. Objective: This study aims to compare the efficacy and safety of eravacycline and other clinically common antibiotics in China, including tigecycline, meropenem, ertapenem, ceftazidime/avibactam+metronidazole, piperacillin/tazobactam, imipenem/cilastatin, and ceftriaxone+metronidazole, for the treatment of adults with cIAIs and to provide a reference for clinical choice. Methods: The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were electronically searched to collect clinical randomized controlled studies (RCTs) comparing different antibiotics in the treatment of patients with cIAIs from inception to June 1, 2021. Two reviewers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. Results: A total of 4050 articles were initially retrieved, and 25 RCTs were included after screening, involving eight treatment therapies and 9372 patients. The results of network meta-analysis showed that in the intention-to-treat (ITT) population, the clinically evaluable (CE) population, and the microbiologically evaluable (ME) population, the clinical response rate of eravacycline was not significantly different from that of the other 7 therapies (P > 0.05). In terms of microbiological response rate, eravacycline was significantly better than tigecycline [tigecycline vs. eravacycline: RR = 0.82, 95%CI (0.65,0.99)], and there was no significant difference between the other 6 regimens and eravacycline (P > 0.05). In terms of safety, the incidence of serious adverse events, discontinuation rate, and all-cause mortality of eravacycline were not significantly different from those of the other 7 treatment therapies (P > 0.05). Conclusion: Based on the evidence generated by the current noninferiority clinical trial design, the efficacy and safety of eravacycline for the treatment of adults with cIAIs are not significantly different from those of the other 7 commonly used clinical antibiotics in China. In terms of microbiological response rate, eravacycline was significantly better than tigecycline. In view of the severe multidrug-resistant situation in China, existing drugs have difficulty meeting the needs of clinical treatment, and the new antibacterial drug eravacycline may be one of the preferred options for the treatment of cIAIs in adults.

Trends in Antibiotic Duration for Complicated Intra-Abdominal Infections : Adaptation to Current Guidelines.

INTRODUCTION: The 2017 surgical infection society (SIS) guidelines recommend 4 days of antibiotic therapy after source control for complicated intra-abdominal infections (cIAIs). Inappropriate exposure to antibiotics has a negative impact on outcomes in individual patients and populations. The goal of this study was to evaluate our institution's practice patterns and adherence to current antibiotic guidelines. METHODS: Medical records from 2010 to 2018 for cIAIs were examined. Complicated appendicitis and complicated diverticulitis cases were included. Exclusion criteria included other etiologies of IAIs, pediatric cases, and cancer operations. RESULTS: Fifty-nine complicated appendicitis cases and 96 complicated diverticulitis cases were identified. For all cases, antibiotic duration prior to publication of the SIS guidelines was significantly longer than post-SIS duration (appendicitis: 12.6 ± 1.1 days pre-SIS [n = 37] vs 9.0 ± 1.1 days post-SIS [n = 22], P = .01; diverticulitis: 15.1 ± 0.8 days pre-SIS [n = 49] vs 11.2 ± 0.5 post-SIS [n = 47], P = .04). Surgical management (SM) was associated with shorter duration of postsource control antibiotic exposure compared with percutaneous drainage (PD) for both appendicitis (SM 10.0 ± 1.2 days vs PD 13.4 ± 1.0 days, P = .02) and diverticulitis (SM 12.8 ± 1.5 days vs PD 16.0 ± 1.5, P = .07). Patients with complicated appendicitis received shorter duration of antibiotics when managed by acute care surgeons compared to general surgeons (8.4 ± 1.1 vs 11.9 ± 0.8, P = .02). CONCLUSION: Despite improvements after the SIS guidelines' publication, the antibiotic duration is still longer than recommended. Surgical intervention and management by acute care specialists were associated with a shorter duration of antibiotic exposure.

A randomized controlled trial comparing the efficacy of tigecycline versus meropenem in the treatment of postoperative complicated intra-abdominal infections.

BACKGROUND: The efficacy and safety of tigecycline in the treatment of complicated intra-abdominal infections (cIAIs) is potentially controversial. Here we conducted the non-inferiority study to assess the efficacy and safety of tigecycline versus meropenem in the treatment of postoperative cIAIs. METHODS: Data of abdominal tumor surgery patients with postoperative cIAIs admitted to intensive care unit (ICU) between October 2017 and December 2019 were collected. A prospective, randomized controlled trial was conducted in which 56 eligible patients with cIAIs randomly received intravenous tigecycline or meropenem for 3 to 14 days. Patients and clinicians were not blinded to the group allocation. RESULTS: The total of 56 patients were enrolled, which were divided into 2 groups, one group included 30 patients receiving meropenem and another group included 26 receiving tigecycline therapy. The 2 groups were similar at demographic and baseline clinical characteristics. Microorganisms were isolated from 46 of 56 patients (82.14%), with a total of 107 pathogens were cultured in two groups. The two groups had similar distribution of infecting microorganisms. The primary end point was the clinical response at the end-oftherapy (EOT) visit and upon discharge visit and comprehensive efficacy. The clinical success rates were 83.33%, 76.67% for meropenem versus 76.92%, 88.46% for tigecycline at the EOT visit and upon discharge visit (P>0.05), respectively. Comprehensive efficacy did not significantly differ between two groups either. There were no significant differences in 30-day and 60-day all-cause mortality between two groups (P>0.05). The univariable analysis identified that serum albumin at admission ICU, colorectal cancer on oncology type, postoperative abdominal bleeding were the risk factors for 60-day all-cause mortality. The multivariable analysis showed that postoperative abdominal bleeding were independent predictors of 60-day all-cause mortality. Gastrointestinal disorders and antibacterials-induced Fungal Infection were the most frequently reported adverse events (AEs). The incidence of AEs was similar between meropenem and tigecycline groups (P>0.05). CONCLUSIONS: Taken together, the study demonstrated that tigecycline is as effective and safe as meropenem for postoperative cIAIs in abdominal tumors patients. Tigecycline is non-inferior to meropenem.

Efficacy and Tolerability of Eravacycline in Bacteremic Patients with Complicated Intra-Abdominal Infection: A Pooled Analysis from the IGNITE1 and IGNITE4 Studies.

Background: Eravacycline is a novel, fully synthetic fluorocycline antibiotic that was evaluated for the treatment of complicated intra-abdominal infections (cIAI) in two phase 3 clinical trials. The objective of this analysis was to evaluate the clinical cure and microbiologic response at the test-of-cure (TOC) visit and the safety of eravacycline in patients with cIAI and baseline bacteremia who received eravacycline versus comparators. Patients and Methods: Pooled data of patients with bacteremia from the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE) 1 and IGNITE4 studies were analyzed. All patients were randomly assigned in a one-to-one ratio to receive eravacycline 1 mg/kg intravenously every 12 hours, ertapenem 1 g intravensouly every 24 hours (IGNITE1), or meropenem 1 g intravenously every eight hours (IGNITE4) for four to 14 days. Blood and intra-abdominal samples were collected from all patients at baseline. Clinical outcome and microbiologic eradiation at the TOC visit (28 days after randomization) and safety in the microbiologic-intent-to-treat population (micro-ITT) were assessed. Results: Of 415 patients treated with eravacycline and 431 treated with carbapenem comparators, concurrent bacteremia was identified in 32 (7.7%) and 31 (7.2%) patients, respectively. Demographic and baseline characteristics were similar among treatment groups. In the micro-ITT population, the pooled clinical response at the TOC visit for eravacycline was 28 of 32 (87.5%) and was 24 of 31 (77.0%) for comparators among the subgroup with baseline bacteremia (treatment difference 5.9; 95% confidence interval [CI], -6.5 to 17.4). At TOC, microbiologic eradication of pathogens isolated from blood specimens occurred for 34 of 35 (97.1%) pathogens with eravacycline and 35 of 36 (97.2%) pathogens with comparators. The incidence of adverse events was comparable between treated groups and similar to that observed in the non-bacteremic population. Conclusion: Eravacycline demonstrated a similar clinical outcome and microbiologic eradication rate as comparator carbapenems in patients with cIAI and associated secondary bacteremia. Future clinical trials of cIAI should report outcomes of this important clinical cohort (cIAI with concurrent bacteremia) given their high risk for adverse outcomes.

Clinical and Microbiologic Efficacy and Safety of Imipenem/Cilastatin/Relebactam in Complicated Infections: A Meta-analysis.

BACKGROUND: Antimicrobial resistance is on the rise. The use of redundant and inappropriate antibiotics is contributing to recurrent infections and resistance. Newer antibiotics with more robust coverage for Gram-negative bacteria are in great demand for complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs), hospital-acquired bacterial pneumonia (HABP), and ventilator-associated bacterial pneumonia (VABP). MATERIALS AND METHODS: We performed this meta-analysis to evaluate the efficacy and safety profile of a new antibiotic, Imipenem/cilastatin/relebactam, compared to other broad-spectrum antibiotics for complicated infections. We conducted a systemic review search on PubMed, Embase, and Central Cochrane Registry. We included randomized clinical trials-with the standard of care as comparator arm with Imipenem/cilastatin/relebactam as intervention arm. For continuous variables, the mean difference was used. For discrete variables, we used the odds ratio. For effect sizes, we used a confidence interval of 95%. A P-value of less than 0.05 was used for statistical significance. Analysis was done using a random-effects model irrespective of heterogeneity. Heterogeneity was evaluated using the I² statistic. RESULTS: The authors observed similar efficacy at clinical and microbiologic response levels on early follow-up and late follow-up compared to the established standard of care. The incidence of drug-related adverse events, serious adverse events, and drug discontinuation due to adverse events were comparable across both groups. CONCLUSION: Imipenem/cilastatin/relebactam has a non-inferior safety and efficacy profile compared to peer antibiotics to treat severe bacterial infections (cUTIs, cIAIs, HABP, VABP).

Novel Beta-Lactam/Beta-Lactamase Plus Metronidazole vs Carbapenem for Complicated Intra-abdominal Infections: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Complicated intra-abdominal infections (cIAIs) remain a leading cause of death in surgical wards, in which antibiotic treatment is crucial. We aimed to compare the efficacy and safety of novel ß-lactam/ß-lactamase inhibitors (BL/BLIs) in combination with metronidazole and carbapenems in the treatment of cIAIs. METHODS: A comprehensive search of randomized controlled trials (RCTs) was performed using Medline, Embase, and Cochrane Library, which compared the efficacy and safety of novel BL/BLIs and carbapenems for the treatment of cIAIs. RESULTS: Six RCTs consisting of 2254 patients were included. The meta-analysis showed that novel BL/BLIs in combination with metronidazole had a lower clinical success rate (risk difference [RD], -0.05; 95% CI, -0.07 to -0.02; I 2 = 0%) and a lower microbiological success rate (RD, -0.04; 95% CI, -0.08 to -0.00; I 2 = 0%). No difference was found between the 2 groups in incidence of adverse events (RD, 0.02; 95% CI, -0.01 to 0.06; I 2 = 0%), serious adverse events (SAEs; RD, 0.01; 95% CI, -0.02 to 0.03; I 2 = 0%), or mortality (RD, 0.01; 95% CI, -0.00 to 0.02). However, ceftazidime/avibactam had a higher risk of vomiting (RD, 0.03; 95% CI, 0.01 to 0.05; I 2 = 47%), and the ceftolozane/tazobactam subgroup showed a higher incidence of SAEs (RD, 0.12; 95% CI, 0.01 to 0.03). CONCLUSIONS: The efficacy of novel BL/BLIs in combination with metronidazole was not as high as that of carbapenems. Although no significant differences were found with respect to overall adverse events, SAEs, or mortality, the novel BL/BLIs has a higher risk of vomiting. We still need to be cautious about the clinical application of a new anti-infective combination. TRIAL REGISTRATION: PROSPERO ID: 42020166061.

The use of ceftolozane-tazobactam in the treatment of complicated intra-abdominal infections and complicated urinary tract infections-A meta-analysis of randomized controlled trials.

OBJECTIVE: The aim of this study was to assess the clinical efficacy and safety of ceftolozane-tazobactam in the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs) in adult patients through meta-analysis. METHODS: PubMed, Embase and Cochrane databases were searched up to June 2019. Only randomized controlled trials (RCTs) that evaluated ceftolozane-tazobactam and comparators for treating cIAIs and cUTIs in adult patients were included. Primary outcome was clinical cure rate; secondary outcomes were clinical failure rate, microbiological eradication rate, and risk of an adverse event (AE). RESULTS: Three RCTs were included. Overall, ceftolozane-tazobactam had a clinical cure rate similar to comparators in the microbiological intent-to-treat (mITT) population (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.43-1.79; I2 = 73%) and in the clinically evaluable (CE) population (OR, 1.22; 95% CI, 0.79-1.88; I2 = 0%). Furthermore, ceftolozane-tazobactam had a similar microbiological eradication rate for pathogens (OR, 1.31; 95% CI, 0.42-4.10; I2 = 37%). There were no significant differences in the risks of treatment-emergent AEs (OR, 1.04; 95% CI, 0.87-1.23; I2 = 0%), serious AEs (OR, 1.16; 95% CI, 0.67-1.99; I2 = 37%), discontinuation of study drug due to an AE (OR, 0.77; 95% CI, 0.17-3.47) and mortality (OR, 1.62; 95% CI, 0.69-3.77, I2 = 0%) between ceftolozane-tazobactam and comparators. CONCLUSIONS: The clinical efficacy of ceftolozane-tazobactam is as high as that of comparators in the treatment of cIAIs and cUTIs in adult patients, and this antibiotic is well tolerated.

Prevalence, predictors, and consequences of inappropriate empiric antimicrobial therapy for complicated urinary tract and intra-abdominal infections in Winnipeg hospitals.

Information on inappropriate empiric antimicrobial therapy (ET) in Canadian hospitals is scarce. All Manitobans 18 years of age and over who were admitted to a hospital in Winnipeg with a complicated urinary tract infection (cUTI) or complicated intra-abdominal infection (cIAI) from January 2006 to December 2014 were eligible for inclusion in this cohort study. The prevalence of inappropriate ET was 11% for cUTI patients and 9% for cIAI patients. The risk of receiving inappropriate ET was higher for older patients (cUTI patients 65 or older had 2-fold increased risk compared to younger patients; odds ratio 2.1, 95% confidence interval 1.3-3.6; this was 1.6 [0.7-3.5] for cIAI patients) and those hospitalized in the previous year: 1.5 (1.0-2.4) in cUTIs and 1.5 (0.6-3.4) in cIAIs. The risk for a hospital stay over 3 weeks was increased for inappropriate ET in cUTI patients, 2.3 (1.4-3.7), but not in cIAI patients, 0.9 (0.4-2.1).

Carbapenems vs ß-Lactam Monotherapy or Combination Therapy for the Treatment of Complicated Intra-abdominal Infections: Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Complicated intra-abdominal infections (cIAIs) result in significant morbidity, mortality, and cost. Carbapenem-resistant sepsis has increased dramatically in the last decade, resulting in infections that are difficult to treat and associated with high mortality rates. To prevent further antibacterial resistance, it is necessary to use carbapenem selectively. The objective of this study was to compare the effectiveness and safety of carbapenems vs alternative ß-lactam monotherapy or combination therapy for the treatment of cIAIs. METHODS: The PubMed, Embase, Medline (via Ovid SP), and Cochrane library databases were systematically searched. We included randomized controlled trials (RCTs) comparing carbapenems vs alternative ß-lactam monotherapy or combination therapy for the treatment of cIAIs. RESULTS: Twenty-two studies involving 7720 participants were included in the analysis. There were no differences in clinical treatment success (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.71-1.05; I 2 = 35%), microbiological treatment success (OR, 0.88; 95% CI, 0.71-1.09; I 2 = 25%), adverse events (OR, 0.98; 95% CI, 0.87-1.09; I 2 = 17%), or mortality (OR, 0.96; 95% CI, 0.68-1.35; I 2 = 7%). Patients.treated with imipenem were more likely to experience clinical or microbiological failure than those treated with alternative ß-lactam monotherapy or combination therapy. CONCLUSIONS: No differences in clinical outcomes were observed between carbapenems and noncarbapenem ß-lactams in cIAIs. Patients treated with imipenem were more likely to experience clinical or microbiological failure than those treated with alternative ß-lactam monotherapy or combination therapy.

Polymicrobial Bacteremia Involving Klebsiella pneumoniae in Patients with Complicated Intra-Abdominal Infections: Frequency, Co-Pathogens, Risk Factors, and Clinical Outcomes.

Background: Klebsiella pneumoniae has gained notoriety because of its high antibiotic resistance and mortality. We compared the clinical features and outcomes of polymicrobial bacteremia involving K. pneumoniae (PBKP). Patients and Methods: A retrospective observational study of patients with polymicrobial and monomicrobial bacteremia involving K. pneumoniae from January 2012 to December 2016 was performed. The expression of resistance and virulence genes of 27 strains was also compared by polymerase chain reaction (PCR). Results: Among the polymicrobial group, the most common accompanying micro-organism was Escherichia coli. No differences in the expression of resistance and virulence genes was found among the 27 strains collected from the group. The analysis of the outcomes revealed that the patients with PBKP were more likely to have recurrent blood stream infections (p = 0.038), longer intensive care unit (ICU) lengths of stay (p = 0.043), and a higher total hospitalization cost (p = 0.045). However, no substantial differences in mortality were found between the two groups. The multivariable analysis revealed that a longer hospital stay prior to the onset of bacteremia (>20 days) was an independent risk factor for PBKP (p = 0.034), and the Sequential Organ Failure Assessment (SOFA) score upon onset of infection (p = 0.013), the adequacy of source control (p < 0.001), and iron supplementation (p = 0.003) were identified as independent predictors of mortality in patients with KP bacteremia. Conclusions: The development of septic shock and the concomitant use of iron supplementation are associated with higher mortality in patients with KP bacteremia, and PBKP did not increase the mortality of these patients, possibly because of the ability of K. pneumoniae to obscure the effects of other bacteria. Thus, adequate source control is more important than high-dose antibiotic therapy and is linked to higher survival.

Ceftolozane/tazobactam for the treatment of complicated intra-abdominal and urinary tract infections: current perspectives and place in therapy.

The current prevalence of infections caused by multidrug-resistant (MDR) organisms is a global threat, and thus, the development of new antimicrobial agents with activity against these pathogens is a healthcare priority. Ceftolozane-tazobactam (C/T) is a new combination of a cephalosporin with a ß-lactamase inhibitor that shows excellent in vitro activity against a broad spectrum of Enterobacteriaceae and Pseudomonas aeruginosa, including extended spectrum ß-lactamase-producing (ESBL) strains and MDR or extensively drug-resistant (XDR) P. aeruginosa. In phase III randomized clinical trials, C/T demonstrated similar efficacy to meropenem for the treatment of complicated intra-abdominal infections (cIAIs) and superior efficacy to levofloxacin for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis. The drug is generally safe and well tolerated and its PK/PD profile is very favorable. Observational studies with C/T have revealed good efficacy for the treatment of different types of infection caused by MDR or XDR P. aeruginosa, including some that originated from the digestive or urinary tracts. The place of C/T in therapy is not well defined, but its use could be recommended in a carbapenem-sparing approach for the treatment of infections caused by ESBL-producing strains or for the treatment of infections caused by P. aeruginosa if there are no other more favorable therapeutic options. Further clinical experience is needed to position this new antimicrobial drug for the empirical treatment of cIAIs or cUTIs.