Complicated Intra-abdominal Infections Research Articles

Meta-analysis of Outcomes Using Ceftolozane-Tazobactam and Ceftazidime-Avibactam for Multidrug-Resistant Organism Infections

Background: Ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (C/A) are new β-lactam/β-lactamase combination antibiotics that were approved by the FDA in 2014 and 2015, respectively, to treat complicated intra-abdominal and urinary tract infections. They are commonly used to treat multidrug-resistant Pseudomonas aeruginosa (MDRPA) and carbapenem-resistant Enterobacteriaceae (CRE) infections at any site. Both medications are also often used as salvage therapy when empiric therapy has failed or when the infectious organism tests resistant to all other available antibiotics. The purpose of this review is to present the clinical experience and reported clinical success rates of C/T and C/A. Methods: PubMed, EMBASE, and Google Scholar were searched from January 1, 2013, through October 1, 2019, for publications detailing clinical experience with C/T and C/A in patients with CRE and MDRPA infections. Included study designs were extended cases series and clinical observational studies. Information on infection type, bacterial agent, salvage therapy uses, clinical success, and resistance development during treatment were abstracted. Meta-regression analysis was used to determine the pooled effectiveness of C/T and C/A among included studies. Results: The literature search returned 1,645 publications. After exclusion criteria were applied, 16 publications representing 769 patients were retained. The study population was mostly male (pooled average, 62%). The major comorbidities represented in the pooled population were solid organ transplantation (20.0%), kidney disease (19.5%), cardiovascular disease (15.3%), and diabetes (15.3%). Pneumonia was the predominant infection type (41.4%) and MDRPA was the pathogen most frequently evaluated (57.7%). The pooled clinical success rate was 70.2% (95% CI, 64.5%–75.3%). Also, 10 studies explicitly evaluated C/A or C/T as salvage therapy. The pooled clinical success rate for salvage therapy studies was 75.2% (95% CI, 69.7%–80.0%). Development of resistance to C/T or C/A during or after treatment was reported for 2.0% of the population. Conclusion: Overall, these medications have a high clinical success rate in patients with severe and complicated infections and limited treatment options. Pooled clinical success rates were high (70.2%) and the medications were particularly effective as salvage therapy. Resistance rates were low, although this could have been biased by the small percentage of studies that reported on this outcome. More longitudinal studies comparing the effectiveness of C/T and C/A against other antibiotic regimens are needed.Funding: NoneDisclosures: None

Eravacycline, a novel tetracycline derivative, does not induce Clostridioides difficile infection in an in vitro human gut model.

The approval of new antibiotics is essential to combat infections caused by antimicrobial-resistant pathogens; however, such agents should be tested to determine their effect on the resident microbiota and propensity to select for opportunistic pathogens, such as Clostridioides difficile. Eravacycline is a new antibiotic for the treatment of complicated intra-abdominal infections. Here, we determined the effects of eravacycline compared with moxifloxacin on the microbiota and if these were conducive to induction of C. difficile infection (CDI). We seeded in vitro chemostat models, which simulate the physiological conditions of the human colon, with a human faecal slurry and instilled gut-reflective concentrations of either eravacycline or moxifloxacin. Eravacycline instillation was associated with decreased Bifidobacterium, Lactobacillus and Clostridium species, which recovered 1 week after exposure. However, Bacteroides spp. levels decreased to below the limit of detection and did not recover prior to the end of the experiment. Post-eravacycline, a bloom of aerobic bacterial species occurred, including Enterobacteriaceae, compared with pre-antibiotic, which remained high for the duration of the experiment. These changes in microbiota were not associated with induction of CDI, as we observed a lack of C. difficile spore germination and thus no toxin was detected. Moxifloxacin exposure sufficiently disrupted the microbiota to induce simulated CDI, where C. difficile spore germination, outgrowth and toxin production were seen. These model data suggest that, despite the initial impact of eravacycline on the intestinal microbiota, similar to clinical trial data, this novel tetracycline has a low propensity to induce CDI.

Antimicrobial Resistance and Molecular Patterns in Community-acquired Complicated Intra-abdominal Infections: A Multicentric Study

Antimicrobial Resistance and Molecular Patterns in Community-acquired Complicated Intra-abdominal Infections: A Multicentric Study

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

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. 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. 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). 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.

Association between postoperative fluid balance and mortality and morbidity in critically ill patients with complicated intra-abdominal infections: a retrospective study.

BackgroundPostoperative fluid overload may increase the risk of developing pulmonary complications and other adverse outcomes. We evaluated the impact of excessive fluid administration on postoperative outcomes in critically ill patients.MethodsWe reviewed the medical records of 320 patients admitted to intensive care unit (ICU) after emergency abdominal surgery for complicated intra-abdominal infection (cIAI) between January 2013 and December 2018. The fluid balance data of the patients were reviewed for a maximum of 7 days. The patients were grouped based on average daily fluid balance with a cutoff value of 20 ml/kg/day. Propensity score matching was performed to reduce the underlying differences between the groups.ResultsPatients with an average daily fluid balance of ≥20 ml/kg/day were associated with higher rates of 30-day mortality (11.8% vs. 2.4%; P=0.036) than those with lower fluid balance (<20 ml/kg/day). Kaplan-Meier survival curves for 30-day mortality in these groups also showed a better survival rate in the lower fluid balance group with a statistical significance (P=0.020). The percentage of patients who developed pulmonary consolidation during ICU stay (47.1% vs. 24.7%; P=0.004) was higher in the fluid-overloaded group. Percentages of newly developed pleural effusion (61.2% vs. 57.7%; P=0.755), reintubation (18.8% vs. 10.6%; P=0.194), and infectious complications (55.3% vs. 49.4%; P=0.539) showed no significant differences between the two groups.ConclusionsPostoperative fluid overload in patients who underwent emergency surgery for cIAI was associated with higher 30-day mortality and more frequent occurrence of pulmonary consolidation. Postoperative fluid balance should be adjusted carefully to avoid adverse clinical outcomes.

In vitro activity of eravacycline against common ribotypes of Clostridioides difficile.

BackgroundEravacycline is a novel synthetic fluorocycline antibacterial approved for complicated intra-abdominal infections.ObjectivesThe purpose of this study was to assess the in vitro activities of eravacycline and comparator antibiotics against contemporary clinical isolates of Clostridioides difficile representing common ribotypes, including isolates with decreased susceptibility to metronidazole and vancomycin.MethodsClinical C. difficile strains from six common or emerging ribotypes were used to test the in vitro activities of eravacycline and comparator antibiotics (fidaxomicin, vancomycin and metronidazole) by broth microdilution. In addition, MBC experiments, time–kill kinetic studies and WGS experiments were performed.ResultsA total of 234 isolates were tested, including ribotypes RT001 (n = 37), RT002 (n = 41), RT014-020 (n = 39), RT027 (n = 42), RT106 (n = 38) and RT255 (n = 37). MIC50/90 values were lowest for eravacycline (≤0.0078/0.016 mg/L), followed by fidaxomicin (0.016/0.063 mg/L), metronidazole (0.25/1.0 mg/L) and vancomycin (2.0/4.0 mg/L). MBCs were lower for eravacycline compared with vancomycin for all ribotypes tested. Both vancomycin and eravacycline demonstrated bactericidal killing, including for epidemic RT027. The presence of the tetM or tetW resistance genes did not affect the MIC of eravacycline.ConclusionsThis study demonstrated potent in vitro activity of eravacycline against a large collection of clinical C. difficile strains that was not affected by ribotype, susceptibility to vancomycin or the presence of certain tet resistance genes. Further development of eravacycline as an antibiotic to be used in patients with Clostridioides difficile infection is warranted.

Elucidating the Molecular Basis of Avibactam-Mediated Inhibition of Class A β-Lactamases.

Disseminating antibiotic resistance rendered by bacteria against the widely used β-lactam antibiotics is a serious concern for public health care. The development of inhibitors for drug-resistant β-lactamase enzymes is vital to combat this rapidly escalating problem. Recently, the U.S. Food and Drug Administration approved a non-β-lactam inhibitor called avibactam for the treatment of complicated intra-abdominal and urinary tract infections caused by drug-resistant Gram-negative bacteria. This work sheds light on the molecular origin of the inhibitory effect of avibactam against the drug-resistant CTX-M variant of class A β-lactamases. In particular, we probed the structural evolution, dynamics features, and energetics along the acylation and deacylation reaction pathways through enhanced sampling molecular dynamics methods and free-energy calculations. We scrutinized the roles of active site residues, the nature of the carbamoyl linkage formed in the inhibitor-enzyme covalent intermediate, and other structural features of the inhibitor molecule. By unraveling the reasons behind the inhibition of all the deacylation routes, we can explain various experimental structural and kinetics data, and propose a way to design new inhibitors based on the β-lactam framework.

Ceftazidime-Avibactam Combination Therapy Compared to Ceftazidime-Avibactam Monotherapy for the Treatment of Severe Infections Due to Carbapenem-Resistant Pathogens: A Systematic Review and Network Meta-Analysis.

Ceftazidime-avibactam (CZA) is a novel beta-lactam beta-lactamase inhibitor combination approved for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and for hospital-acquired/ventilator-associated pneumonia. The aim of this systematic review (PROSPERO registration number: CRD42019128927) was to evaluate the effectiveness of CZA combination therapy versus CZA monotherapy in the treatment of severe infections. The databases included in the search, until 12 February 2020, were MEDLINE by PubMed, EMBASE, and The Cochrane Central Register of Controlled Trials. We included both randomized controlled trials (RCTs) and non-randomized studies published in peer-reviewed journals and in the English language. The primary outcome was all-cause mortality (longest follow-up) evaluated in patients with the diagnosis of infection with at least one pathogen; secondary outcomes were clinical and microbiological improvement/cure. Thirteen studies were included in the qualitative synthesis: 7 RCTs and 6 retrospective studies All the six retrospective studies identified carbapenamase-producing Enterobacteriaceae (CRE) as the cause of infection and for this reason were included in the network meta-analysis (NMA); the quality of the studies, assessed using the New Castle-Ottawa Scale, was moderate-high. In all the six retrospective studies included in the NMA, CZA was used in large part for off-label indications (mostly blood stream infections: 80–100% of patients included). No difference in mortality rate was observed in patients undergoing CZA combination therapy compared to CZA monotherapy [n = 503 patients, direct evidence OR: 0.96, 95% CI: 0.65–1.41].

Safety Profile of Ceftazidime-Avibactam: Pooled Data from the Adult Phase II and Phase III Clinical Trial Programme.

IntroductionCeftazidime–avibactam combines the established anti-pseudomonal cephalosporin, ceftazidime, with the novel non-β-lactam β-lactamase inhibitor, avibactam.ObjectivesThe aim of this study was to evaluate the safety of ceftazidime–avibactam in adults using pooled data from two phase II (NCT00690378, NCT00752219) and five phase III (NCT01499290, NCT01726023, NCT01644643, NCT01808093 and NCT01595438/NCT01599806) clinical studies.MethodsSafety data from seven multicentre, randomised, active-comparator studies were pooled by study group at the patient level for descriptive analyses, comprising patients with complicated urinary tract infection (cUTI), including pyelonephritis, complicated intra-abdominal infection (cIAI), or nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), treated with ceftazidime–avibactam ± metronidazole or comparator.ResultsIn total, 4050 patients (ceftazidime–avibactam ± metronidazole, n = 2024; comparator, n = 2026) were included in the pooled analysis. Adverse events (AEs) up to the last study visit occurred in 996 (49.2%) and 965 (47.6%) patients treated with ceftazidime–avibactam ± metronidazole and comparator, respectively. The most common AEs across treatment groups were diarrhoea, nausea, headache, vomiting and pyrexia. There were few discontinuations due to AEs (2.5% and 1.7% for ceftazidime–avibactam ± metronidazole and comparators, respectively). Overall rates of serious AEs were 8.7% for ceftazidime–avibactam ± metronidazole and 7.2% for comparators; respective rates of AEs with an outcome of death were 2.0% and 1.8%. AEs considered causally related to the study drug or procedures occurred in 10.7% and 9.6% of patients treated with ceftazidime–avibactam ± metronidazole and comparators; the most common drug-related AEs in both groups were diarrhoea, headache, nausea and increased alanine aminotransferase. No impact to the safety profile of ceftazidime–avibactam ± metronidazole was found with regard to intrinsic factors, such as age or renal function at baseline, or extrinsic factors, such as geographical origin. Potentially clinically significant changes in laboratory parameters were infrequent with no trends or safety concerns identified.ConclusionThe observed safety profile of ceftazidime–avibactam across infection types is consistent with the established safety profile of ceftazidime monotherapy and no new safety findings were identified. This analysis supports the use of ceftazidime–avibactam as a treatment option in adults with cUTI, cIAI and NP, including VAP.Electronic supplementary materialThe online version of this article (10.1007/s40264-020-00934-3) contains supplementary material, which is available to authorized users.

Evaluation of the Etest and disk diffusion method for detection of the activity of ceftazidime-avibactam against Enterobacterales and Pseudomonas aeruginosa in China

BackgroundCeftazidime-avibactam was approved in China in 2019 for treating complicated intra-abdominal infections, hospital-acquired pneumonia, ventilator-associated pneumonia, and infections caused by Enterobacterales and Pseudomonas aeruginosa for which treatment options are limited. However, no currently available commercial systems have been approved for antimicrobial susceptibility testing of ceftazidime-avibactam in China. Here, we evaluated the Etest and disk diffusion method for detecting the activity of ceftazidime-avibactam against Enterobacterales and P. aeruginosa in China.ResultsIn total, 194 Enterobacterales and 77 P. aeruginosa isolates, which were divided into a random selection group (140 Enterobacterales and 46 P. aeruginosa isolates) and stock group (54 Enterobacterales and 31 P. aeruginosa isolates), were assessed by the Etest, disk diffusion and broth microdilution methods. Minimum inhibitory concentrations and zone diameters were interpreted according to the CLSI supplement M100 30th edition. For all 271 tested isolates, no very major errors were found by using Etest, whereas the overall major error rate was 2.0% (4/203). The overall categorical agreement rates of Etest for Enterobacterales and P. aeruginosa were 99.5% (193/194) and 96.1% (74/77), respectively, and the essential agreement rates were 95.9% (186/194) and 94.8% (73/77), respectively. The disk diffusion method showed that the very major error and major error rates were 1.5% (3/204) and 2.5% (5/203), respectively. Overall categorical agreement rates values of the disk diffusion method for Enterobacterales and P. aeruginosa were 98.5% (191/194) and 93.5% (72/77) compared with broth microdilution, respectively.ConclusionsFor Enterobacterales and P. aeruginosa, both the Etest and disk diffusion method showed acceptable performance as alternatives to the standard broth microdilution method for clinical treatment interpretation. Application of the disk diffusion method in Enterobacterales was slightly better than that in P. aeruginosa.

An Evaluation of Treatment Patterns and Associated Outcomes Among Adult Hospitalized Patients With Lower-Risk Community-Acquired Complicated Intra-abdominal Infections: How Often Are Expert Guidelines Followed?

BackgroundExpert guidelines discourage use of antipseudomonal β-lactams and fluoroquinolones in lower-risk patients with community-acquired complicated intra-abdominal infection (CA cIAI). Compliance with these recommendations across US hospitals is unclear. This study sought to determine treatment patterns and associated outcomes among adult hospitalized lower-risk patients with CA cIAI.MethodsA study using data from the Premier Healthcare Database (10/2015–12/2017) was performed. Inclusion criteria: age ≥18 years; hospitalized; had a cIAI at admission; and received antibiotics within the first 4 hospital days. Patients were excluded if they were high risk, were transferred from another health care facility, had a recent hospital admission, or received dialysis within 30 days of admission. Empiric antibiotic treatment patterns and associated outcomes were quantified.ResultsOverall, 46 722 (66%) patients with cIAIs met the lower-risk CA IAI study criteria. Among lower-risk CA IAI patients, the mean (SD) age was 53.4 (18.2) years, and 71% had a Charlson Comorbidity Index score of 0. The most common diagnosis was acute appendicitis with peritonitis (59.7%). Among lower-risk CA IAI patients, 54% received piperacillin/tazobactam, 20% received a fluoroquinolone (FQ), 11% received ceftriaxone, and 7% received ampicillin/sulbactam. Overall, the median hospital length of stay was 4 days and median costs were $12 345 USD. Nearly 90% of patients were discharged home, and <1% died. Outcomes were similar across all empiric treatments received.ConclusionsOveruse of antipseudomonal β-lactams and fluoroquinolones was commonplace among lower-risk CA IAI patients. These findings can serve as the basis for an antimicrobial stewardship initiative in hospitals aspiring to reduce the use of broad-spectrum antibiotics.

Role of Antifungal Therapy in Complicated Intra-abdominal Infections

In this narrative review, we discuss key questions about the antifungal treatment of complicated intrabdominal infections (cIAI). Although less common than bacteria, Candida spp. are not an infrequent cause of cIAI. Considering that invasive abdominal candidiasis (IAC) may be accompanied by septic shock in up to 40% of cases, empirical antifungal treatment should be considered while waiting for rapid tests and cultures results, and it should be guided by the presence of risk factors for invasive candidiasis in patients with consistent signs and symptoms. Early antifungal therapy before availability of culture results can be partly based on the results of rapid diagnostic tests such as antigen/antibody assays or other rapid methods, although it should be noted that most data pertaining to the use of rapid tests refer to candidemia or invasive candidiasis in general, and not specifically to IAC, thus clinical judgment still remains crucial. Although cultures are hampered by a slow turnaround time, they remain of paramount importance, by allowing identification at species level and antifungal susceptibility testing. Together with source control, adequate antifungal therapy is an essential component of the correct approach to IAC. Future research should focus on enriching our knowledge on the diagnostic performance of rapid tests in cIAI, and on providing a standardized definition for IAC. Advancements in these fields are crucial for improving the correct use of antifungals at the bedside of cIAI patients and also for reducing unnecessary antifungal use in line with antifungal stewardship principles.

Activity of ceftolozane-tazobactam and comparators when tested against bacterial surveillance isolates collected from patients at risk of infections caused by resistant gram-negative pathogens

Ceftolozane-tazobactam is an antipseudomonal cephalosporin combined with a β-lactamase inhibitor. Ceftolozane-tazobactam has been approved for treatment of complicated urinary tract infections and acute pyelonephritis, for complicated intra-abdominal infections (with metronidazole) in adults, and for hospital-acquired bacterial pneumonia including ventilator-associated bacterial pneumonia. This study analyzed gram-negative pathogen susceptibility in US and European patients who are considered at risk for infections caused by pathogens resistant to commonly used antimicrobials: patients in the intensive care unit (ICU), patients on the hematology/oncology or transplant service who may be immunocompromised, and patients >65 years old (yo). ICU patients had the lowest susceptibility for Enterobacterales and PSA. The susceptibility for isolates from the immunocompromised and >65 yo groups was similar. Ceftolozane-tazobactam was the most active agent against PSA, with ≥90%S for >65 yo and immunocompromised, and >80%S for ICU. Meropenem and ceftolozane-tazobactam were the most active agents against Enterobacterales.

Utility of World Society of Emergency Surgery Sepsis Severity Score in Predicting Outcomes of Intra-abdominal Infections

Background: Intra-abdominal infections are classified as simple or complicated. Many tools have been studied to predict risk factors and outcomes of patients with intra-abdominal infections. None of these tools has been adopted for patient care at the Kenyatta National Hospital (KNH), Kenya.&#x0D; Objective: To determine the utility of the World Society of Emergency Surgery (WSES) Sepsis Severity Score in predicting short-term outcomes of patients managed for complicated intra-abdominal infections.&#x0D; Methods: We conducted a hospital-based prospective cohort study. Patients aged 18 years and above with complicated intra-abdominal infections were recruited. Data were obtained on demographics, condition at admission, time to source control, origin of infection, immune suppressants and complications. IBM SPSS version 21.0 was used to obtain means and standard deviations while logistic regression was used for associations.&#x0D; Results: A sepsis severity score of 6.5, best predicted mortality having a sensitivity of 80% and a specificity of 20.9% were obtained. For each unit increase in the WSES scores, the odds of mortality were 2.1, organ dysfunction 2.2, CCU admission 2.1.&#x0D; Conclusion: Our sepsis severity score has demonstrated good performance in our adult population, and also ability to predict adverse outcomes other than mortality in patients managed for intra-abdominal sepsis.&#x0D; Keywords: WSES, Sepsis, Sepsis severity score, Intra-abdominal infections

Burden of Complicated Intra-Abdominal Infections in Children in Nigeria: Recent Experience and Systematic Review.

Background: Intra-abdominal infections encompass a wide range of conditions from uncomplicated appendicitis to fecal peritonitis. Little is known about the burden of complicated intra-abdominal infection (cIAIs) in children in low- and middle-income countries (LMICs). Method: This a report of recent experience and a systematic review of the burden in Nigeria. Results: Of 85 children with cIAIs, the most common primary cause was typhoid intestinal perforation (54; 63.5%) and complicated appendicitis (20; 23.5%). The complication rate after surgery was high, including surgical site infection (SSI) in 49 (57.6%), post-operative intra-abdominal abscess in 14 (16.5%), and complete abdominal wound dehiscence in 13 (15.3%). The rate of re-operation was 19 (22.4%) and 12 (14.1%) patients required re-admission for adhesion intestinal obstruction and unresolved SSI. Eight (9.4%) died from overwhelming infection. Systematic review revealed only a few publications, but these were mostly on specific causes of cIAIs and publications providing comprehensive data are lacking. Conclusion: Investment in research into cIAIs in children in LMICs is needed. Efforts need to be focused on the role of source control in reducing the high complication rate and mortality.

Simultaneous administration of imipenem/cilastatin/relebactam with selected intravenous antimicrobials, a stewardship approach

Imipenem/cilastatin/relebactam is a β-lactam/β-lactamase inhibitor that has been recently FDA approved for complicated intra-abdominal and urinary tract infections under the brand name Recarbrio®. It has activity against imipenem non-susceptible Pseudomonas species as well as KPC-producing Enterobacteriaceae. Optimization of PK/PD of antimicrobials particularly in critically-ill patients is essential, but unfortunately, is hindered by separate administration that requires significant resources. The objective of the study is to investigate the compatibility of Y-site administration of imipenem/cilastatin/relebactam with a wide range of antimicrobials. After admixture, physical characteristics, pH changes and turbidity were measured for each 2-drug combination at a time. With the exception of amphotericin B deoxycholate, and posaconazole, imipenem/cilastatin/relebactam was compatible with a variety of antimicrobial agents. The compatibility profile described, will facilitate incorporation into hospital protocols, contribute to therapy optimization and guide clinicians to avoid successive administration, consequently resulting in reduction of total infusion time, optimization of PK/PD, economizing nursing time and cost containment.

The Quick Sequential Organ Failure Assessment (qSOFA) Score is a Poor Mortality Predictor in Patients with Complicated Intra-abdominal Infections

BACKGROUND: Despite the evolution in surgical treatment and antimicrobial therapy in the last years the complicated intra-abdominal infections (cIAIs) are still associated with high morbidity and mortality. Different scoring systems are already available for early prognostic evaluation and yet none has been widely accepted.&#x0D; AIM: Our aim was to evaluate the prognostic accuracy of quick sequential organ failure assessment (qSOFA), one of the most recent scores, in patients with cIAIs.&#x0D; MATERIALS AND METHODS: We studied retrospectively 110 patients with cIAIs admitted to the Department of Surgical Diseases (DSD) at University Hospital “Prof. Dr. Stoyan Kirkovich” Stara Zagora from January 2017 to July 2019. Area under receiver operating characteristics (AUROC) curves of systemic inflammatory response syndrome (SIRS), qSOFA, and Mannheim Peritonitis Index (MPI) were analyzed and a comparison of ROC curves was performed to explore their prognostic performance.&#x0D; RESULTS: Twenty-five (22.7%) patients died during hospitalization. qSOFA score showed poor prognostic accuracy (AUROC = 0.698, 95% CI = 0.566–0.829), worse than MPI score (AUROC = 0.698 vs. 0.844), but better than SIRS (AUROC = 0.698 vs. 0.583). The qSOFA score ≥2 points was observed with lack of sensitivity (32.0%) as outcome predictor. ROC curve analysis showed prognostic inferiority of qSOFA compared to MPI (difference between areas = 0.146, p = 0.0232).&#x0D; CONCLUSION: In patients with cIAIs, quick-SOFA score was observed with poor prognostic performance.

Tigecycline Therapy for Infections Caused by Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae in Critically Ill Patients.

We aimed to evaluate tigecycline on the clinical effectiveness in treating complicated skin and soft tissue infections (cSSTI), complicated intra-abdominal infections (cIAI), and pneumonia, caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, as data are limited. From three medical centers in Taiwan, we retrospectively studied the cSSTI, cIAI, and/or pneumonia caused by ESBL-producing Enterobacteriaceae. Among the 71 patients, including 39 patients infected with Klebsiella pneumoniae, 30 infected with Escherichia coli and others, the clinical success rate of tigecycline-based therapy was 80–90% for pneumonia and cSSTI caused by E. coli and 50–60% for cIAI caused by K. pneumoniae and E. coli. Microbiological and clinical outcome of pneumonia caused by carbapenem-resistant K. pneumoniae was poor. Univariate Cox analysis showed that dyspnea, SOFA score, septic shock, thrombocytopenia, prolonged prothrombin time, and lesser microbiological eradication were significant factors associated with 30-day mortality after the end of therapy. Cox regression proportional hazards model revealed dyspnea and a SOFA score > 8 to be independently associated with time to death. For ESBL producers, tigecycline showed good effects for cSSTI and pneumonia by E. coli, ordinary for cIAI, but ineffective for pneumonia by K. pneumoniae. Dyspnea and a high SOFA score predict a poor outcome.

Ceftolozane/Tazobactam for Treating Children With Exacerbations of Cystic Fibrosis Due to Pseudomonas aeruginosa: A Review of Available Data.

Ceftolozane-tazobactam is a novel fifth-generation cephalosporin/β-lactamase inhibitor combination recently approved for treatment of both complicated intra-abdominal and urinary tract infections in adults. Considering its potent bactericidal activity against Pseudomonas aeruginosa, it might represent an important option also for treating children with exacerbations of cystic fibrosis due to Pseudomonas aeruginosa when other alternative treatments have been exhausted. We hereby review available data on the use of ceftolozane-tazobactam in children, focusing on cystic fibrosis.

Preclinical Pharmacokinetic/Pharmacodynamic Studies and Clinical Trials in the Drug Development Process of EMA-Approved Antibacterial Agents: A Review.

Development of new antibacterial agents is necessary as drug-resistant bacteria are a threat to global health. In Europe, the European Medicines Agency has been guiding this development process for more than two decades. We investigated preclinical and clinical pre-approval studies to illuminate the current authorization process with emphasis on pharmacokinetic/pharmacodynamic approaches and clinical phases. All centrally authorized systemic antibacterial and antimycobacterial drugs within the European Union were included without any time restriction. Additionally, US Food and Drug Administration-approved antibiotics of the previous 3 years, which were not yet approved by the European Medicines Agency, were included. We focused on preclinical pharmacokinetic/pharmacodynamic studies and phase II and phase III clinical trials. Furthermore, we looked at the recommended dosing regimens and approved indications. In this review, we designed tree diagrams as a new means of illustrating the development process of antibiotics to relate pharmacokinetic/pharmacodynamic phase II and III studies to approved indications. We included 23 (European Medicines Agency, 18; US Food and Drug Administration, 5) antimicrobial agents. Tetracyclines, carbapenems, and cephalosporins were the leading classes. The recommended dosing intervals were significantly shorter in time- vs exposure-dependent drugs (median 8 vs 12, p = 0.006). The majority of approved indications (i.e., acute bacterial skin and soft-tissue infection, community-acquired pneumonia, complicated intra-abdominal infection, complicated urinary tract infection, and complicated skin and soft-tissue infection) used non-inferiority trials. Phase II and III clinical trials investigating community-acquired pneumonia involved the fewest patients. Some promising drugs were marketed in recent years; the individual steps to their authorizations are illuminated. We confirmed the relevance of preclinical pharmacokinetic/pharmacodynamic studies in dosing optimization and decision making in antimicrobial drug development. Non-inferiority clinical trials predominated.