[Progress in the treatment of intra-abdominal anaerobic infection].

Most abdominal infections are mixed infections caused by aerobic and anaerobic bacteria. Anaerobic infections are characterized by rancid secretions or abscess formation. Early implementation of source control is the key in the treatment of abdominal anaerobic infections. Damage control should be followed as one of the principles of surgical treatment. As the in vitro isolation and culture of anaerobic bacteria as well as its drug sensitivity test are time-consuming and sometimes inaccurate, the treatment of anaerobic bacteria infection is mostly empirical. Anti-infective therapy should be employed once anaerobic bacteria infection is confirmed. Ertapenem, Mosifloxacin, and Cefoperazone-sulbactam can be used for first-line monotherapy, while combination therapy can use second- or third-generation Cephalosporin, Quinolones plus Nitroimidazoles. Nutritional support and anti-shock treatment should not be neglected when implementing surgical control of infection source and antimicrobial therapy. Considering the increasing drug resistance of anaerobic bacteria, and the higher drug resistance rate in China as compared to western countries, the choice of antibiotics should be made rationally and based on epidemiological characteristics of anaerobic bacteria in different regions.

Eravacycline for the treatment of complicated intra-abdominal infections.

Introduction: Complicated intra-abdominal infections (cIAIs) are among the most frequent infections, contributing to significant morbidity and healthcare costs. Several medical needs remain unmet, related to the pharmacokinetic capacities of the available drugs and their limited spectrum of activity for targeting multidrug-resistant Gram-negative and Gram-positive bacteria. Eravacycline, a new synthetic fluorocycline, could have useful properties in cIAIs.Areas covered: The antimicrobial activity of eravacycline against the microorganisms most frequently cultured in cIAIs has been confirmed in worldwide panels of clinical isolates, including enterococci, ESBL-producing Enterobacteriaceae, Acinetobacter baumannii and anaerobes. Pharmacokinetic data demonstrate interesting characteristics with good tissue concentrations including biliary tract and digestive tissues. At a conventional dosage of 1 mg/kg q12h, no adjustment is required on the basis of race or gender, or in elderly (≥ 65 years old) patients, patients with renal impairment or patients undergoing hemodialysis. Phase 2 and 3 trials assessing the clinical efficacy and safety of eravacycline demonstrated non-inferiority versus carbapenems and a good safety profile.Expert opinion: Eravacycline may be particularly suitable for the treatment of cIAIs. Results from clinical trials and real-world data are now expected in specific subgroups of patients to confirm the safety profile and efficacy observed in registration trials.

Eravacycline: a new treatment option for complicated intra-abdominal infections in the age of multidrug resistance.

Aim: Recently approved for use in complicated intra-abdominal infection, eravacycline is a novel fluorocycline with broad spectrum of activity against resistant Gram-negative pathogens. This manuscript is a pooled analysis of two Phase III trials. Clinical efficacy: Clinical cure rates were 86.8% for eravacycline versus 87.6% for ertapenem, and 90.8% for eravacycline versus 91.2% for meropenem in the Intent to Treat (micro-ITT) populations, and 87.0% for eravacycline versus 88.8% ertapenem, and 92.4 versus 91.6% for meropenem in the Modified Intent to Treat (MITT) populations. Safety: Eravacycline is well tolerated, with lower rates of nausea, vomiting and diarrhea than other tetracyclines. Conclusion: Eravacycline is an effective new option for use in complicated intra-abdominal infections, and in particular, for the treatment of extended-spectrum ß-lactamase- and carbapenem-resistant Enterobacteriaceae-expressing organisms.

Safety and Efficacy of Ceftazidime-Avibactam Plus Metronidazole in the Treatment of Children ≥3 Months to <18 Years With Complicated Intra-Abdominal Infection: Results From a Phase 2, Randomized, Controlled Trial.

BACKGROUND: Ceftazidime-avibactam plus metronidazole is effective in the treatment of complicated intra-abdominal infection (cIAI) in adults. This single-blind, randomized, multicenter, phase 2 study (NCT02475733) evaluated the safety, efficacy and pharmacokinetics of ceftazidime-avibactam plus metronidazole in children with cIAI. METHODS: Hospitalized children (≥3 months to <18 years) with cIAI were randomized 3:1 to receive intravenous ceftazidime-avibactam plus metronidazole, or meropenem, for a minimum of 72 hours (9 doses), with optional switch to oral therapy thereafter for a total treatment duration of 7-15 days. Safety and tolerability were assessed throughout the study, along with clinical and microbiologic outcomes, and pharmacokinetics. A blinded observer determined adverse event (AE) causality, and clinical outcomes up to the late follow-up visit. RESULTS: Eighty-three children were randomized and received study drug (61 ceftazidime-avibactam plus metronidazole and 22 meropenem); most (90.4%) had a diagnosis of appendicitis. Predominant Gram-negative baseline pathogens were Escherichia coli (79.7%) and Pseudomonas aeruginosa (33.3%); 2 E. coli isolates were ceftazidime-non-susceptible. AEs occurred in 52.5% and 59.1% of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. Serious AEs occurred in 8.2% and 4.5% of patients, respectively; none was considered drug related. No deaths occurred. Favorable clinical/microbiologic responses were observed in ≥90% of patients in both treatment groups at end-of-intravenous treatment and test-of-cure visits. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was well tolerated, with a safety profile similar to ceftazidime alone, and appeared effective in pediatric patients with cIAI due to Gram-negative pathogens, including ceftazidime-non-susceptible strains.

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.

Monitoring the antimicrobial susceptibility of Gram-negative organisms involved in intraabdominal and urinary tract infections recovered during the SMART study (Spain, 2016 and 2017).

OBJECTIVE: Continuous antimicrobial resistance surveillance is recommended by Public Health authorities. We up-dated data from the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance study in Spain. METHODS: The antimicrobial susceptibility data and extended-spectrum beta-lactamase (ESBL) production in isolates recovered from intra-abdominal (IAI) (n=1,429) and urinary tract (UTI) (n=937) infections during the 2016- 2017 SMART study in 10 Spanish hospitals were analysed. RESULTS: Escherichia coli was the most frequently microorganism isolated (48.3% and 53.7%) followed by Klebsiella spp. (11.5% and 21.9%) in IAIs and UTIs, respectively. Figures for Pseudomonas aeruginosa were 9.0% and 6.1%, being more frequently recovered from patients with nosocomial infections. Overall, 9.9% (IAI) and 14.0% (UTI) of E. coli, Klebsiella spp. and Proteus mirabilis isolates were ESBL-producers, being Klebsiella pneumoniae (34.5%) from UTI of nosocomial origin the most frequent. ESBL-producers were higher in patients >60 years in both IAIs and UTIs. As in previous years, amikacin (96.3%-100% susceptibility), ertapenem (84.2%-100%) and imipenem (70.3%- 100%) were the most active antimicrobials tested among Enterobacterales species. The activity of amoxicillin-clavulanic, piperacillin-tazobactam, and ciprofloxacin susceptibility was lower, particularly among ESBL-producers. Ertapenem susceptibility (88.9%-100%) was retained in ESBL-E. coli isolates that were resistant to these antimicrobials but decreased (28.6%-100%) in similar isolates of K. pneumoniae. CONCLUSIONS: Continuous antimicrobial resistance surveillance from the SMART study reveals overall maintenance of ESBL-producers in Spain, although with higher presence in isolates from UTIs than from IAIs. Moreover, ertapenem activity was high in E. coli irrespective of ESBL production but decreased in K. pneumoniae, particularly among ESBL-producers.

Antimicrobial susceptibilities of specific syndromes created with organ-specific weighted incidence antibiograms (OSWIA) in patients with intra-abdominal infections.

BACKGROUND: The aim was to evaluate the value of organ-specific weighted incidence antibiogram (OSWIA) percentages for bacterial susceptibilities of Gram-negative bacteria (GNB) collected from intra-abdominal infections (IAIs) during SMART 2010-2014. METHODS: We retrospectively calculated the OSWIA percentages that would have been adequately covered by 12 common antimicrobials based on the bacterial compositions found in the appendix, peritoneum, colon, liver, gall bladder and pancreas. RESULTS: The ESBL positive rates were 65.7% for Escherichia coli, 36.2% for Klebsiella pneumoniae, 42.9% for Proteus mirabilis and 33.1% for Klebsiella oxytoca. Escherichia coli were mainly found in the appendix (76.8%), but less so in the liver (32.4%). Klebsiella pneumoniae constituted 45.2% of the total liver pathogenic bacteria and 15.2-20.8% were found in 4 other organs, except the colon and appendix (< 10%). The percentages of Pseudomonas aeruginosa infections were higher in the gall bladder, intra-abdominal abscesses, pancreas and colon (10.2-13.2%) and least (5.4%) in the appendix. The susceptibilities of hospital acquired (HA) and community acquired (CA) IAI isolates from appendix, gall bladder and liver showed ≥80% susceptibilities to amikacin (AMK), imipenem (IPM), piperacillin-tazobactam (TZP) and ertapenem (ETP), while the susceptibility of isolates in abscesses and peritoneal fluid showed ≥80% susceptibility only to amikacin (AMK) and imipenem (IPM). In colon CA IAI isolates susceptibilities did not reach 80% for AMK and ETP, and in pancreatic IAIs susceptibilities of HA GNBs did not reach 80% to AMK, TZP and ETP, and CA GNBs to IMP and ETP. In addition, besides circa 80% susceptibility of HA and CA IAI isolates from appendix to cefoxitin (FOX), IAI isolates from all other organs had susceptibilities between 7.6 and 67.9% to all cephalosporins tested, 28.3-75.2% to fluoroquinolones and 7.6-51.0% to ampicillin-sulbactam (SAM), whether they were obtained from CA or HA infections. CONCLUSION: The calculated OSWIA susceptibilities were specific for different organs in abdominal infections.

Clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa: pooled data from the ceftazidime/avibactam Phase III clinical trial programme.

Objectives: This analysis evaluated the clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa isolates pooled from the adult Phase III clinical trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI) or nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP). Methods: Baseline isolates from five Phase III randomized controlled trials of ceftazidime/avibactam versus predominantly carbapenem comparators in patients with cIAI (RECLAIM 1 and 2; NCT01499290 and RECLAIM 3; NCT01726023), cUTI (RECAPTURE 1 and 2; NCT01595438 and NCT01599806), NP including VAP (REPROVE; NCT01808092) and cIAI or cUTI caused by ceftazidime-non-susceptible Gram-negative pathogens (REPRISE; NCT01644643) were tested for MDR status and susceptibility to ceftazidime/avibactam and carbapenem-based comparators using CLSI broth microdilution methodology. Microbiological and clinical responses for patients with ≥1 MDR Enterobacteriaceae or P. aeruginosa isolate were assessed at the test-of-cure (TOC) visit. Results: In the pooled microbiologically modified ITT population, 1051 patients with MDR Enterobacteriaceae and 95 patients with MDR P. aeruginosa isolates were identified. Favourable microbiological response rates at TOC for all MDR Enterobacteriaceae and MDR P. aeruginosa were 78.4% and 57.1%, respectively, for ceftazidime/avibactam and 71.6% and 53.8%, respectively, for comparators. The proportions of patients with ≥1 MDR isolate who were clinically cured at TOC were similar in the ceftazidime/avibactam (85.4%) and comparator (87.9%) arms. Conclusions: Ceftazidime/avibactam demonstrated similar clinical efficacy to predominantly carbapenem comparators against MDR Enterobacteriaceae and P. aeruginosa, and may be a suitable alternative to carbapenem-based therapies for cIAI, cUTI and NP/VAP caused by MDR Gram-negative pathogens.

In Vitro Activity of Ceftazidime-Avibactam against Isolates from Patients in a Phase 3 Clinical Trial for Treatment of Complicated Intra-abdominal Infections.

The increasing prevalence of multidrug-resistant Gram-negative pathogens has generated a requirement for new treatment options. Avibactam, a novel non-ß-lactam-ß-lactamase inhibitor, restores the activity of ceftazidime against Ambler class A, C, and some class D ß-lactamase-producing strains of Enterobacteriaceae and Pseudomonas aeruginosa The in vitro activities of ceftazidime-avibactam versus comparators were evaluated against 1,440 clinical isolates obtained in a phase 3 clinical trial in patients with complicated intra-abdominal infections (cIAI; ClinicalTrials.gov identifier NCT01499290). Overall, in vitro activities were determined for 803 Enterobacteriaceae, 70 P. aeruginosa, 304 Gram-positive aerobic, and 255 anaerobic isolates obtained from 1,066 randomized patients at baseline. Susceptibility was determined by broth microdilution. The most commonly isolated Gram-negative, Gram-positive, and anaerobic pathogens were Escherichia coli (n = 549), Streptococcus anginosus (n = 130), and Bacteroides fragilis (n = 96), respectively. Ceftazidime-avibactam was highly active against isolates of Enterobacteriaceae, with an overall MIC90 of 0.25 mg/liter. In contrast, the MIC90 for ceftazidime alone was 32 mg/liter. The MIC90 value for ceftazidime-avibactam (4 mg/liter) was one dilution lower than that of ceftazidime alone (8 mg/liter) against isolates of Pseudomonas aeruginosa The ceftazidime-avibactam MIC90 for 109 ceftazidime-nonsusceptible Enterobacteriaceae isolates was 2 mg/liter, and the MIC range for 6 ceftazidime-nonsusceptible P. aeruginosa isolates was 8 to 32 mg/liter. The MIC90 values were within the range of susceptibility for the study drugs permitted per the protocol in the phase 3 study to provide coverage for aerobic Gram-positive and anaerobic pathogens. These findings demonstrate the in vitro activity of ceftazidime-avibactam against bacterial pathogens commonly observed in cIAI patients, including ceftazidime-nonsusceptible Enterobacteriaceae (This study has been registered at ClinicalTrials.gov under identifier NCT01499290.).

Clinical experience with ceftazidime/avibactam for treatment of antibiotic-resistant organisms other than Klebsiella pneumoniae.

BACKGROUND: Ceftazidime/avibactam is a newly approved ß-lactam/ß-lactamase inhibitor combination with activity against antibiotic-resistant Gram-negative organisms, including many carbapenem-resistant strains. Although this agent may offer a promising treatment option for serious infections with limited alternatives available, clinical experience with ceftazidime/avibactam in treatment of infections caused by multidrug-resistant Gram-negative organisms other than Klebsiella pneumoniae is limited. METHODS: A retrospective case series was performed to evaluate patients treated with ceftazidime/avibactam for infections caused by organisms other than K. pneumoniae at our institution over a 1-year period. Patients aged at least 18 years who received at least one dose of ceftazidime/avibactam were eligible for inclusion. Clinical and microbiological data were collected, and investigators assessed adverse effects, microbiological cure, clinical success, and 30-day in-hospital mortality following completion of ceftazidime/avibactam therapy. RESULTS: Ten patients were included. The most common index infection was pneumonia (n = 6/13, 46%) and the most frequently isolated organism was Pseudomonas aeruginosa (n = 8/21, 38%). Fifty percent of patients received ceftazidime/avibactam as monotherapy. Microbiological cure was achieved in 67% (n = 6/9) of patients and 70% (n = 7/10) of patients met criteria for clinical success. The 30-day in-hospital mortality rate was 30%. No patients experienced adverse events because of ceftazidime/avibactam therapy. CONCLUSIONS: For infections caused by antibiotic-resistant Gram-negative organisms other than K. pneumoniae, clinical and microbiological success rates for patients treated with ceftazidime/avibactam were similar to those that have been reported for K. pneumoniae. Ceftazidime/avibactam appears to be a promising treatment option for infections caused by a variety of resistant Gram-negative organisms when limited alternatives exist.

Moxifloxacin in Pediatric Patients With Complicated Intra-abdominal Infections: Results of the MOXIPEDIA Randomized Controlled Study.

BACKGROUND: This study was designed to evaluate primarily the safety and also the efficacy of moxifloxacin (MXF) in children with complicated intra-abdominal infections (cIAIs). METHODS: In this multicenter, randomized, double-blind, controlled study, 451 pediatric patients aged 3 months to 17 years with cIAIs were treated with intravenous/oral MXF (N = 301) or comparator (COMP, intravenous ertapenem followed by oral amoxicillin/clavulanate; N = 150) for 5 to 14 days. Doses of MXF were selected based on the results of a Phase 1 study in pediatric patients (NCT01049022). The primary endpoint was safety, with particular focus on cardiac and musculoskeletal safety; clinical and bacteriologic efficacy at test of cure was also investigated. RESULTS: The proportion of patients with adverse events (AEs) was comparable between the 2 treatment arms (MXF: 58.1% and COMP: 54.7%). The incidence of drug-related AEs was higher in the MXF arm than in the COMP arm (14.3% and 6.7%, respectively). No cases of QTc interval prolongation-related morbidity or mortality were observed. The proportion of patients with musculoskeletal AEs was comparable between treatment arms; no drug-related events were reported. Clinical cure rates were 84.6% and 95.5% in the MXF and COMP arms, respectively, in patients with confirmed pathogen(s) at baseline. CONCLUSIONS: MXF treatment was well tolerated in children with cIAIs. However, a lower clinical cure rate was observed with MXF treatment compared with COMP. This study does not support a recommendation of MXF for children with cIAIs when alternative more efficacious antibiotics with better safety profile are available.

Efficacy ratio: A tool to enhance optimal antimicrobial use for intra-abdominal infections.

BACKGROUND: Antimicrobial resistance and inappropriate antibiotic regimen hamper a favorable outcome in intra-abdominal infections. Clinicians rely on the minimum inhibitory concentration (MIC) value to choose from the susceptible antimicrobials. However, the MIC values cannot be directly compared between the different antibiotics because their breakpoints are different. For that reason, efficacy ratio (ER), a ratio of susceptible MIC breakpoint and MIC of isolate, can be used to choose the most appropriate antimicrobial. MATERIALS AND METHODS: A prospective, observational study conducted during 2015 and 2016 included 356 Escherichia coli and 158 Klebsiella spp. isolates obtained from the intra-abdominal specimens. MIC was determined by microbroth dilution method, and ER of each antibiotic was calculated for all the isolates. RESULTS: For both E. coli and Klebsiella spp., ertapenem, amikacin, and piperacillin/tazobactam had the best activities among their respective antibiotic classes. DISCUSSION: This is the first study calculating ER for deciding empiric treatment choices. ER also has a potential additional value in choosing the use of susceptible drugs as monotherapy or combination therapy. A shift in ERs over a period of time tracks rising MIC values and predicts antimicrobial resistance development. CONCLUSION: Estimation of ER could be a meaningful addition for the interpretation of an antimicrobial susceptibility report, thus helping the physician to choose the best among susceptible antimicrobials for patient management.

Do bacteria isolated from ICU patients 'ESKAPE' antibiotic treatment? In vitro susceptibility of the Enterobacteriaceae family to tigecycline.

BACKGROUND: Enterobacteriaceae are currently causing the majority of healthcare-associated infections (HAI) and simultaneously expressing increasing levels of antibiotic resistance. The purpose of this study is to assess the in vitro sensitivity of MDR strains from the family Enterobacteriaceae to tigecycline in relation to their origin from patients hospitalized in intensive care units (ICUs) and non-ICUs. METHODS: The study involved 156 clinically significant strains of the Enterobacteriaceae family isolated from patients with complicated intraabdominal infections (cIAIs) and/or complicated skin and skin structure infections (cSSSIs) hospitalized in ICUs and other surgical departments. Tigecycline MICs were determined by Etest. RESULTS: The highest percentage of tigecycline non-susceptible (intermediate + resistant strains) in vitro strains among the Enterobacteriaceae species were observed for Serratia spp. 77.3%, followed by Citrobacter spp. (76.9%) and Enterobacter spp. (70%); whereas K. pneumoniae and E. coli showed 73-73.8% tigecycline susceptibility rates. CONCLUSION: Tigecycline demonstrates a high level of antimicrobial in vitro activity when tested against E. coli and K. pneumoniae, even those with the ESBL-phenotype. Tigecycline retained activity against merely 22-30% of Enterobacter, Citrobacter and Serratia genera.

EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA): a protocol of a European multicentre observational study.

INTRODUCTION: The rapid worldwide spread of carbapenem-resistant Enterobacteriaceae (CRE) constitutes a major challenge. The aim of the EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA), which is part of the Innovative Medicines Initiative Joint Undertaking (IMI JU) funded COMBACTE-CARE project, is to investigate risk factors for and outcome determinants of CRE infections to inform randomised clinical trial designs and to provide a historical cohort that could eventually be used for future comparisons with new drugs targeting CRE. METHODS: A multicentre (50 sites), multinational (11 European countries), analytical observational project was designed, comprising 3 studies. The aims of study 1 (a prospective cohort study) include characterising the features, clinical management and outcomes of hospitalised patients with intra-abdominal infection, pneumonia, complicated urinary tract infections and bloodstream infections caused by CRE (202 patients in each group). The main outcomes will be 30-day all-cause mortality and clinical response. Study 2 (a nested case-control study) will identify the risk factors for target infections caused by CRE; 248 selected patients from study 1 will be matched with patients with carbapenem-susceptible Enterobacteriaceae (1:1) and with hospitalised patients (1:3) and will provide a historical cohort of patients with CRE infections. Study 3 (a matched cohort study) will follow patients in study 2 in order to assess mortality, length of stay and hospital costs associated with CRE. All patients will be followed for 30 days. Different, up-to-date statistical methods will be applied to come to unbiased estimates for all 3 studies. ETHICS AND DISSEMINATION: Before-study sites will be initiated, approval will be sought from appropriate regulatory agencies and local Ethics Committees of Research or Institutional Review Boards (IRBs) to conduct the study in accordance with regulatory requirements. This is an observational study and therefore no intervention in the diagnosis, management or treatment of the patients will be required on behalf of the investigation. Any formal presentation or publication of data collected from this study will be considered as a joint publication by the participating physician(s) and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) for authorship. TRIAL REGISTRATION NUMBER: NCT02709408.

Molecular ß-Lactamase Characterization of Aerobic Gram-Negative Pathogens Recovered from Patients Enrolled in the Ceftazidime-Avibactam Phase 3 Trials for Complicated Intra-abdominal Infections, with Efficacies Analyzed against Susceptible and Resistant Subsets.

The correlation of the clinical efficacy of ceftazidime-avibactam (plus metronidazole) with that of meropenem was evaluated in subjects infected with Gram-negative isolates having characterized ß-lactam resistance mechanisms from the complicated intra-abdominal infection (cIAI) phase 3 clinical trials. Enterobacteriaceae isolates displaying ceftriaxone and/or ceftazidime MIC values of ≥2 µg/ml and Pseudomonas aeruginosa isolates with ceftazidime MIC values of ≥16 µg/ml were characterized for extended-spectrum-ß-lactamase (ESBL) content. Enterobacteriaceae and P. aeruginosa isolates with imipenem and meropenem MIC values of ≥2 and ≥8 µg/ml, respectively, were tested for carbapenemase genes. The primary efficacy endpoint was clinical cure at test of cure (TOC) among the members of the microbiologically modified intention-to-treat (mMITT) population. A total of 14.5% (56/387) and 18.8% (74/394) of patients in the ceftazidime-avibactam and meropenem arms had isolates that met the MIC screening criteria at the baseline visit, respectively. CTX-M variants alone (29.7%; 41/138) or in combination with OXA-1/30 (35.5%; 49/138), most commonly, blaCTX-M group 1 variants (79/90; 87.8%), represented the ß-lactamases most frequently observed among Enterobacteriaceae isolates. Among the patients infected with pathogens that did not meet the screening criteria, 82.2% showed clinical cure in the ceftazidime-avibactam group versus 85.9% in the meropenem group. Among patients infected with any pathogens that met the MIC screening criteria, clinical cure rates at TOC were 87.5% and 86.5% for the ceftazidime-avibactam and meropenem groups, respectively. Ceftazidime-avibactam had clinical cure rates of 92.5% to 90.5% among patients infected with ESBL- and/or carbapenemase-producing Enterobacteriaceae strains at the baseline visit, while meropenem showed rates of 84.9% to 85.4%. The ceftazidime-avibactam and meropenem groups had cure rates of 75.0% and 86.7%, respectively, among patients having any pathogens producing AmpC enzymes. The efficacy of ceftazidime-avibactam was similar to that of meropenem for treatment of cIAI caused by ESBL-producing organisms. (This study has been registered at ClinicalTrials.gov under registration no. NCT01499290 and NCT01500239.).

In vitro activity of ceftazidime/avibactam against urinary isolates from patients in a Phase 3 clinical trial programme for the treatment of complicated urinary tract infections.

Objectives: To evaluate the in vitro activity of ceftazidime/avibactam relative to comparator agents against Gram-negative isolates from a Phase 3 clinical trial programme for complicated urinary tract infections (RECAPTURE). Methods: The in vitro activity of ceftazidime/avibactam was evaluated against 840 Gram-negative pathogens isolated at baseline from 1033 randomized patients in two pivotal Phase 3 clinical trials for the treatment of complicated urinary tract infections. The trials were conducted in 160 institutions from 25 countries worldwide. Susceptibility testing was performed by broth microdilution at a central laboratory according to CLSI methodologies. Results: Overall, ceftazidime/avibactam showed significant activity against the Enterobacteriaceae and Pseudomonas aeruginosa with MIC 90 values of 0.5 and 8 mg/L, respectively. Against the most common Enterobacteriaceae, MIC 90 values were 0.25 mg/L for Escherichia coli , 1 mg/L for Klebsiella pneumoniae , 0.06 mg/L for Proteus mirabilis and 2 mg/L for Enterobacter cloacae . The ceftazidime/avibactam MIC 90 for 154 ceftazidime-non-susceptible isolates of Enterobacteriaceae was 1 mg/L and the ceftazidime/avibactam MIC 90 for 15 non-susceptible isolates of P. aeruginosa was 64 mg/L. There was a significant reduction in the ceftazidime/avibactam MIC relative to ceftazidime alone for most of the Enterobacteriaceae isolates. Conclusions: The ceftazidime/avibactam in vitro activity against these clinical urinary tract isolates demonstrates the potential utility of the drug in complicated urinary tract infections.

Clinical characteristics and antimicrobial patterns in complicated intra-abdominal infections: a 6-year epidemiological study in southern China.

Complicated intra-abdominal infection (cIAIs) are a common and important cause of morbidity worldwide. In this study, the clinical features, microbiological profiles, antimicrobial patterns and treatments of 3233 cIAI patients (mean age, 47.6 years; 54.7% male) with 3531 hospitalisations from 2008-2013 were retrospectively investigated. The most commonly isolated bacteria were Escherichia coli (47.6%), Klebsiella pneumoniae (16.9%), Enterococcus faecalis (10.4%) and Pseudomonas aeruginosa (8.8%). Ciprofloxacin, aminoglycoside (gentamicin), piperacillin/tazobactam and carbapenems exhibited activity against 53%, 76%, 88% and 100% of extended-spectrum ß-lactamase (ESBL)-positive Enterobacteriaceae isolates, respectively. Pseudomonas aeruginosa isolates exhibited 100%, 95%, 88%, 71% and 76% susceptibility to aminoglycoside (gentamicin), ciprofloxacin, meropenem, imipenem and ceftazidime, respectively, and Enterococcus remained 100% susceptible to vancomycin and linezolid. ß-Lactam antibacterials other than penicillin (specifically third-generation cephalosporins) and imidazole derivatives (ornidazole and metronidazole) were the most common first-line treatments. Patients subjected to regimen change after initial antibiotic treatment had predisposing conditions (e.g. older age, more severe co-morbidities) and a higher incidence of P. aeruginosa infection; in addition, these patients encountered a higher average cost of care and worse clinical outcomes compared with those without medication modification. Taken together, these findings indicate the importance of appropriate initial empirical therapy and suggest the use of combination therapy comprising cephalosporins and metronidazole.

In Vitro Activity of Ceftolozane-Tazobactam against Anaerobic Organisms Identified during the ASPECT-cIAI Study.

The in vitro activities of ceftolozane-tazobactam, meropenem, and metronidazole were determined against anaerobic organisms isolated from patients with complicated intraabdominal infections (cIAI) in global phase III studies. Ceftolozane-tazobactam activity was highly variable among different species of the Bacteroides fragilis group, with MIC90 values ranging from 2 to 64 µg/ml. More-potent in vitro activity was observed against selected Gram-positive anaerobic organisms; however, small numbers of isolates were available, and, therefore, the clinical significance of these results is unknown. Variable activity of ceftolozane-tazobactam against anaerobic organisms necessitates use in combination with metronidazole for the treatment of cIAI.

Antimicrobial Susceptibility Of Intra-Abdominal Infection Isolates From A Tertiary Care Hospital In Karachi.

BACKGROUND: Intra-abdominal infections are associated with significant morbidity and mortality. The most frequent pathogens involved are the gastrointestinal flora which can cause poly-microbial infections. Microbiological diagnosis is required to determine the aetiology and antimicrobial susceptibility of the organisms involved. Prompt initiation of antimicrobials is essential for improving patient's outcome. Knowledge of local trends of antimicrobial resistance in nosocomial isolates is essential for empiric therapy. METHODS: A total of 190 clinical isolates collected from intra-abdominal infections during July 2013 to July 2014 were included in the study. Organism identification and Antimicrobial sensitivity testing using standard biochemical tests and CLSI recommended criteria was carried out. RESULTS: Of the total 190 isolates from abdominal infection sources 52% were from fluid sources (peritoneal & ascitic fluid), 41% were from gall bladder and 6.5% were from other abdominal sources. E. coli (46.8%) was the most frequently isolated gram negative and Enterococcus (13.1%) was the most frequently isolated gram positive organism. Carbapenem (imipenem) was the most active agent against enterobacteraceae exhibiting, 94.4% and 91.3% sensitivity against E. coli and Klebsiella respectively. While vancomycin was the most active agent against gram positive organisms. Eighty-four percent of the Enterococci isolated were sensitive to vancomycin. Most isolates exhibited resistance to one or more antibiotics. CONCLUSIONS: Continuous evolution of antimicrobial resistance patterns in bacteria necessitates updating of local data on antimicrobial susceptibility profiles to ensure the safety and efficacy of pathogen specific antimicrobial therapies.

Epidemiology and antimicrobial susceptibility of Gram-negative aerobic bacteria causing intra-abdominal infections during 2010-2011.

The study for monitoring antimicrobial resistance trends (SMART) surveillance program monitors the epidemiology and trends in antibiotic resistance of intra-abdominal pathogens to currently used therapies. The current report describes such trends during 2010-2011. A total of 25,746 Gram-negative clinical isolates from intra-abdominal infections were collected and classified as hospital-associated (HA) if the hospital length of stay (LOS) at the time of specimen collection was ≥48 hours, community-associated (CA) if LOS at the time of specimen collection was <48 hours, or unknown (no designation given by participating centre). A total of 92 different species were collected of which the most common was Escherichia coli: 39% of all isolates in North America to 55% in Africa. Klebsiella pneumoniae was the second most common pathogen: 11% of all isolates from Europe to 19% of all isolates from Asia. Isolates were from multiple intra-abdominal sources of which 32% were peritoneal fluid, 20% were intra-abdominal abscesses, and 16.5% were gall bladder infections. Isolates were further classified as HA (55% of all isolates), CA (39% of all isolates), or unknown (6% of all isolates). The most active antibiotics tested were imipenem, ertapenem, amikacin, and piperacillin-tazobactam. Resistance rates to all other antibiotics tested were high. Considering the current data set and high-level resistance of intra-abdominal pathogens to various antibiotics, further monitoring of the epidemiology of intra-abdominal infections and their susceptibility to antibiotics through SMART is warranted.