Carbapenems In Patients Research Articles

Empirical meropenem versus piperacillin/tazobactam for adult patients with sepsis (EMPRESS) trial: Protocol.

Piperacillin/tazobactam may be associated with less favourable outcomes than carbapenems in patients with severe bacterial infections, but the certainty of evidence is low. The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an investigator-initiated, international, parallel-group, randomised, open-label, adaptive clinical trial with an integrated feasibility phase. We will randomise adult, critically ill patients with sepsis to empirical treatment with meropenem or piperacillin/tazobactam for up to 30 days. The primary outcome is 30-day all-cause mortality. The secondary outcomes are serious adverse reactions within 30 days; isolation precautions due to resistant bacteria within 30 days; days alive without life support and days alive and out of hospital within 30 and 90 days; 90- and 180-day all-cause mortality and 180-day health-related quality of life. EMPRESS will use Bayesian statistical models with weak to somewhat sceptical neutral priors. Adaptive analyses will be conducted after follow-up of the primary outcome for the first 400 participants concludes and after every 300 subsequent participants, with adaptive stopping for superiority/inferiority and practical equivalence (absolute risk difference <2.5%-points) and response-adaptive randomisation. The expected sample sizes in scenarios with no, small or large differences are 5189, 5859 and 2570 participants, with maximum 14,000 participants and ≥99% probability of conclusiveness across all scenarios. EMPRESS will compare the effects of empirical meropenem against piperacillin/tazobactam in adult, critically ill patients with sepsis. Due to the pragmatic, adaptive design with high probability of conclusiveness, the trial results are expected to directly inform clinical practice.

The diagnostic accuracy of the GeneXpert ESBL-ampC prototype assay for rapid PCR-based detection of extended-spectrum beta-lactamase genes directly from urine.

Early identification of complicated urinary tract infections caused by ESBL-producing Enterobacterales has the potential to limit the use of carbapenems to those patients without alternative antibiotic options and avoid the empirical use of carbapenems in patients without ESBL-producing bacteria. The purpose for such a test will differ by setting and ESBL prevalence rates. Countries with low ESBL rates and cephalosporins as empiric treatment (e.g., The Netherlands) will need a rule-in test to decide to use carbapenems, while countries with high ESBL rates and empiric carbapenem treatment will need a rule-out test for ESBLs to de-escalate therapy early. Anyway, such as a test would-at least theoretically-improve patient care and reduce selective pressure for the emergence of carbapenem resistance.

Piperacillin/tazobactam versus carbapenems in patients with severe bacterial infections: A systematic review with meta-analysis.

Piperacillin/tazobactam or meropenem are often used to treat patients with severe bacterial infections. We aimed to compare the desirable and undesirable effects of empirical and/or definitive piperacillin/tazobactam versus carbapenems in patients with severe bacterial infections. We searched PubMed, Embase, CENTRAL, Epistemonikos, and trial registers for randomised clinical trials of empirical and/or definitive piperacillin/tazobactam versus carbapenems in adult patients with severe bacterial infection (i.e., any bacterial infection requiring hospitalisation). The primary outcome was all-cause short-term mortality within 90 days. Secondary outcomes were all-cause long-term mortality, adverse events, quality of life, days alive without or duration of life support, secondary infections, selection of fungi or resistant bacteria, and days alive and out of hospital or hospital length of stay. We calculated relative risks (RRs) using random effects and fixed effect meta-analyses along with trial sequential analyses. We included 31 trials (n=8790 patients) with overall high risk of bias. The RR for all-cause short-term mortality was 1.16 (95% confidence interval [CI]: 0.94-1.43, low certainty evidence), for adverse events 1.00 (98% CI: 0.96-1.04, moderate certainty evidence), for secondary infections 1.13 (98% CI: 0.76-1.68, very low certainty evidence), and for selection of fungi or resistant bacteria 1.61 (98% CI: 0.89-2.89, very low certainty evidence). There were no or limited data for the remaining outcomes. Based on very low or low certainty evidence, piperacillin/tazobactam may be associated with less favourable outcomes in patients with severe bacterial infections as compared with carbapenems, but the information size for a robust conclusion has not been reached.

414. Detection of Colonized Patients with Organisms Resistant to Carbapenems by a Fast Molecular Method at a Hospital in Nicaragua.

Abstract Background The resistance to carbapenems has significant implications regard the clinical outcomes of the patients. Strategies to detect colonized patients with carbapenems-resistant organisms are useful to start isolation measures to prevent intrahospital transmission. GeneXpert Carba-R is a fast molecular test to detect rectal colonization by this type of microorganisms. The aim of this study was to detect colonized patients transferred from other countrywide hospitals in Nicaragua, to have an epidemiological panorama of the circulation of genes that confers resistance to carbapenems. Methods This is a retrospective cohort study in a referral hospital (Hospital Dr. Fernando Vélez Paiz) in Managua, Nicaragua. The period of the study was between January 2020 and October 2020. Patients referred to our ICU that had been stayed more than 48 hours in the originating health-care center were recruited. Rectal swab were processed by GeneXpert Carba-R to identify any of the genes of resistance (NDM, KPC, VIM, IMP, OXA-48). An association between colonization and clinical outcomes was evaluated. Results Eighty-nine patients were included in the study and 27 (30.3%) of them had a positive test of Xpert Carba-R. In four patients more than one gene was detected. The most frequent gene detected was NDM (66.6%). Other detected genes were VIM and KPC. Patients colonized with this kind of microorganims were identified coming from 9 countrywide hospitals and from 6 hospitals of the capital city (Managua). Independent risk factors for colonization by organisms resistant to carbapenems were previous exposition to this class of antibiotic (OR: 9.82; CI95%: 3.29-29.30) and qSOFA ≥ 2 points at the admission (OR: 7.36; CI95%: 2.60-20.76). The mortality in the colonized patients was 33.3% vs 9.6% in the control group (p=0.006), with an odds ratio of 4.6 (CI95%: 1.46-14.90). Map of Nicaragua showing the wide distribution of the detection of genes conferring resistance to carbapenems in patients referred to Hospital Dr. Fernando Vélez Paiz in the capital city of Managua. Conclusion The prevalence of rectal colonization by organisms resistant to carbapenems in patients transferred to a referral hospital in Nicaragua is high. The most frequent gene detected was NDM. There are presence of these genes in countrywide hospitals. The previous use of carbapenems and the severity of the illness at the admission were risk factors for colonization. To be colonized with this microorganism increased the risk to die. Disclosures All Authors: No reported disclosures.

Cerebrospinal fluid concentrations of fluoroquinolones and carbapenems in tuberculosis meningitis.

Background: Tuberculosis meningitis (TBM) is the most lethal form of TB. It is difficult to treat in part due to poor or uncertain drug penetration into the central nervous system (CNS). To help fill this knowledge gap, we evaluated the cerebrospinal fluid (CSF) concentrations of fluoroquinolones and carbapenems in patients being treated for TBM. Methods: Serial serum and CSF samples were collected from hospitalized patients being treated for TBM. CSF was collected from routine lumbar punctures between alternating timepoints of 2 and 6h after drug administration to capture early and late CSF penetration. Rich serum sampling was collected after drug administration on day 28 for non-compartmental analysis. Results: Among 22 patients treated for TBM (8 with confirmed disease), there was high use of fluoroquinolones (levofloxacin, 21; moxifloxacin, 10; ofloxacin, 6) and carbapenems (imipenem, 11; meropenem, 6). Median CSF total concentrations of levofloxacin at 2 and 6h were 1.34mg/L and 3.36mg/L with adjusted CSF/serum ratios of 0.41 and 0.63, respectively. For moxifloxacin, the median CSF total concentrations at 2 and 6h were 0.78mg/L and 1.02mg/L with adjusted CSF/serum ratios of 0.44 and 0.62. Serum and CSF concentrations of moxifloxacin were not affected by rifampin use. Among the 76 CSF samples measured for carbapenem concentrations, 79% were undetectable or below the limit of detection. Conclusion: Fluoroquinolones demonstrated high CSF penetration indicating their potential usefulness for the treatment of TBM. Carbapenems had lower than expected CSF concentrations.

Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial

Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment. This non-inferiority, open-label, multicentre, randomised trial was done in six hospitals in the Netherlands. Adult patients (≥18 years) who were treated with intensive chemotherapy or haematopoietic stem-cell transplantation (HSCT) for a haematological malignancy, and had fever of unknown origin during high-risk neutropenia (<0·5 × 109/L expected for ≥7 days) were eligible. After onset of fever, patients received either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Between 48 h and 72 h of treatment, participants were randomly assigned (1:1) by a computer-generated sequence to receive a short-term (72 h [60-84]; short treatment group) or extended (≥9 days until being afebrile for 5 days or neutrophil recovery; extended treatment group) carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was designed to assess the non-inferiority of the short treatment compared with the extended treatment regimen, with a non-inferiority margin of 10%. The primary outcome was adjudicated by an independent outcome committee, who were masked to treatment allocation, and was analysed in the intention-to-treat and per-protocol populations. The trial is completed and registered with ClinicalTrials.gov, NCT02149329. Between Dec 1, 2014, and July 1, 2019, 281 patients were included in the intention-to-treat analysis: 144 (51%) patients were assigned to the short treatment group and 137 (49%) to the extended treatment group. Median age was 59 years (IQR 52-65); 109 (39%) patients were women and 172 (61%) were men; 205 (73%) patients received HSCT. In the intention-to-treat analysis, 28 (19%) of 144 patients in the short treatment group versus 21 (15%) of 137 patients in the extended treatment group had treatment failure (adjusted risk difference [ARD] 4·0% [90% CI -1·7% to 9·7%]; p=0·25). In the per-protocol analysis (n=225), 24 (23%) of 104 patients in the short treatment group and 19 (16%) of 121 patients in the extended treatment group had treatment failure (ARD 7·3% [0·3% to 14·9%]; p=0·11). The most common grade 3-5 infection-related adverse events were mucositis (23 [20%] of 114 adverse events in the short treatment group vs 28 [29%] of 98 adverse events in the extended treatment group), fever of unknown origin (20 [18%] vs 16 [16%] events), and bacteraemia (15 [13%] vs 13 [13%] events). The number of serious adverse events were higher in the short treatment group (23 [16%] of 144 patients) than in the extended treatment group (14 [10%] of 137 patients), due to an increased rate of readmission (17 [12%] patients in the short treatment group vs ten [7%] in the extended treatment group). Death before 30 days after neutrophil recovery occurred in five (3%) participants in the short treatment group: two due to progressive leukaemia, two due to candidaemia, and one due to Enterococcus faecium bacteraemia and drug-induced pneumonitis. One (1%) patient died in the extended treatment group due to candidaemia. None of the deaths were related to carbapenem-sensitive infections. Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating. The Netherlands Organisation for Health Research and Development and Fonds NutsOhra.

The long and short of antibiotic management for neutropenic fever in patients with haematological malignancy

Neutropenic fever is a common complication of therapy for haematological malignancy and in about 40% of episodes, no clinical focus or microbiological cause is identified. 1 Verlinden A Jansens H Goossens H et al. Safety and efficacy of antibiotic de-escalation and discontinuation in high-risk hematological patients with febrile neutropenia: a single-center experience. Open Forum Infect Dis. 2022; 9ofab624 Crossref PubMed Scopus (6) Google Scholar , 2 Averbuch D Orasch C Cordonnier C et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013; 98: 1826-1835 Crossref PubMed Scopus (343) Google Scholar , 3 Aguilar-Guisado M Espigado I Martín-Peña A et al. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. Lancet Haematol. 2017; 4: e573-e583 Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar The optimal strategy for antibiotic management in the setting of neutropenic fever with no identified source is yet to be defined. Common strategies include early de-escalation from empiric therapy to antibiotic prophylaxis until neutrophil recovery or complete cessation of antibiotic therapy with different cessation thresholds used. 2 Averbuch D Orasch C Cordonnier C et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013; 98: 1826-1835 Crossref PubMed Scopus (343) Google Scholar , 4 Freifeld AG Bow EJ Sepkowitz KA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011; 52: e56-e93 Crossref PubMed Scopus (2014) Google Scholar A cellular recovery threshold (neutrophil count ≥0·5×109/L) for cessation has been recommended, 4 Freifeld AG Bow EJ Sepkowitz KA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011; 52: e56-e93 Crossref PubMed Scopus (2014) Google Scholar but, new data suggest the use of clinically guided cessation using clinical stability and resolution of fever for earlier antibiotic cessation. 1 Verlinden A Jansens H Goossens H et al. Safety and efficacy of antibiotic de-escalation and discontinuation in high-risk hematological patients with febrile neutropenia: a single-center experience. Open Forum Infect Dis. 2022; 9ofab624 Crossref PubMed Scopus (6) Google Scholar , 3 Aguilar-Guisado M Espigado I Martín-Peña A et al. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. Lancet Haematol. 2017; 4: e573-e583 Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar Earlier antibiotic cessation compared with continuation until resolution of neutropenia is associated with lower antibiotic exposure and no significant difference in rates of clinical failure, safety, or mortality. 1 Verlinden A Jansens H Goossens H et al. Safety and efficacy of antibiotic de-escalation and discontinuation in high-risk hematological patients with febrile neutropenia: a single-center experience. Open Forum Infect Dis. 2022; 9ofab624 Crossref PubMed Scopus (6) Google Scholar , 3 Aguilar-Guisado M Espigado I Martín-Peña A et al. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. Lancet Haematol. 2017; 4: e573-e583 Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trialEarly discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating. Full-Text PDF

Comparison of Duration and Empiric Antibiotic Choice of Post-Operative Treatment in Abdominal Sepsis.

Background: Although abdominal foci are the second most common source of sepsis, only few studies focus on the optimal length of post-operative antibiotic therapy in critically ill patients with abdominal sepsis. The aim of this study was to compare the outcomes of short versus long antibiotic therapy as well as broad-spectrum penicillin versus carbapenem in patients with abdominal sepsis. Patients and Methods: We performed a single center retrospective study in patients with abdominal sepsis who underwent emergency surgery. The study was conducted in a tertiary hospital in Germany during 2016-2018. We reviewed the duration of post-operative antibiotic therapy and the initially used agent, comparing patients treated shorter or longer than seven days with or without source control. Depending on the empirically given antibiotic, a subgroup analysis was conducted comparing patients treated with piperacillin-tazobactam versus carbapenems. Results: Longer duration of post-operative antibacterial treatment (>7 days) was not substantially advantageous. The group with a longer course of antibiotic therapy had more severe post-operative complications (82.4% [n = 61] vs. 62.5% [n = 20]; p = 0.01) requiring longer critical care support (18 days vs. 11 days; p = 0.027), prolonging the length of stay (28 days vs. 20 days; p = 0.044). Surgical re-interventions were more frequent in the long-course arm (70.3% vs. 40.6%; p = 0.004). The subgroup analysis comparing piperacillin-tazobactam versus carbapenems confirmed more severe complications (86.3% vs. 67.5%; p = 0.04) for the carbapenem arm. Conclusions: Post-surgical continuation of antibiotic agents beyond seven days was observed with more post-operative complications and delayed recovery. Piperacillin-tazobactam seems to be a potent alternative for patients with abdominal sepsis.

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.

Cross-Reactivity to Cephalosporins and Carbapenems in Penicillin-Allergic Patients: Two Systematic Reviews and Meta-Analyses

There is no recent systematic review on the risk of cross-reactivity to cephalosporins and carbapenems in penicillin-allergic patients despite many new studies on the subject. All past reviews have several limitations such as not including any patient with a T-cell-mediated penicillin allergy. To determine the risk of cross-reactivity to cephalosporins and carbapenems in patients with a proven IgE- or T-cell-mediated penicillin allergy. To measure the association between R1 side chain similarity on cephalosporins and penicillins and the risk of cross-reactivity. MEDLINE and EMBASE were searched from January 1980 to March 2019. Studies had to include at least 10 penicillin-allergic subjects whose allergy had been confirmed by a positive skin test (ST) or drug provocation test (DPT) result. Cross-reactivity had to be assessed to at least 1 cephalosporin or carbapenem through ST or DPT. Both random-effects and fixed-effect models were used to combine data. A bioinformatic model was used to quantify the similarity between R1 side chains. Twenty-one observational studies on cephalosporin cross-reactivity involving 1269 penicillin-allergic patients showed that the risk of cross-reactivity varied with the degree of similarity between R1 side chains: 16.45% (95% CI, 11.07-23.75) for aminocephalosporins, which share an identical side chain with a penicillin (similarity score= 1), 5.60% (95% CI, 3.46-8.95) for a few cephalosporins with an intermediate similarity score (range, 0.563-0.714), and 2.11% (95% CI, 0.98-4.46) for all those with low similarity scores (below 0.4), irrespective of cephalosporin generation. The higher risk associated with aminocephalosporins was observed whether penicillin allergy was IgE- or T-cell-mediated. Eleven observational studies on carbapenem cross-reactivity involving 1127 penicillin-allergic patients showed that the risk of cross-reactivity to any carbapenem was 0.87% (95% CI, 0.32-2.32). Although it remains possible that these meta-analyses overestimated the risk of cross-reactivity, clinicians should consider the increased risk of cross-reactivity associated with aminocephalosporins, and to a lesser extent with intermediate-similarity-score cephalosporins, compared with the very low risk associated with low-similarity-score cephalosporins and all carbapenems when using beta-lactams in patients with a suspected or proven penicillin allergy.

Carbapenem versus Cefepime or Piperacillin-Tazobactam for Empiric Treatment of Bacteremia Due to Extended-Spectrum-β-Lactamase-Producing Escherichia coli in Patients with Hematologic Malignancy.

Infections with extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli are common in patients with hematologic malignancy. The utility of cefepime and piperacillin-tazobactam as empiric therapy for ESBL-producing E. coli bacteremia in patients with hematologic malignancy is largely unknown. We conducted a single-center, retrospective cohort review of 103 adult inpatients with leukemia and/or hematopoietic stem cell transplant (HCT) recipients with monomicrobial ESBL-producing E. coli bacteremia. No association between increased 14-day mortality and empiric treatment with cefepime (8%) or piperacillin-tazobactam (0%) relative to that with carbapenems (19%) was observed (P = 0.19 and P = 0.04, respectively). This observation was consistent in multivariate Cox proportional hazards models adjusted for confounding and an inverse probability of treatment-weighted (IPTW) Cox proportional hazards model. Both fever and persistent bacteremia were more common in patients treated empirically with cefepime or piperacillin-tazobactam. Empiric treatment with cefepime or piperacillin-tazobactam did not result in increased mortality relative to that with treatment with carbapenems in patients with hematologic malignancy and ESBL-producing E. coli bacteremia, although most patients were changed to carbapenems early in treatment. However, due to prolonged fever and persistent bacteremia, their role may be limited in this patient population.

Looking back 2018--focused on surgical infection

The published clinical research in 2018 in surgical infection are changing current opinions in the management of acute appendicitis, antibiotics usage, resuscitation of septic shock, and choice of nutritional therapy in critically ill patients. In the management of uncomplicated acute appendicitis, antibiotic therapy can be successful in selected patients who wish to avoid surgery. Delayed primary wound closure can not reduce superficial surgical site infection rates compared to primary wound closure for complicated appendicitis. Infusion of antibiotics 30 minutes before the start of operation may influence their prophylactic effect on surgical site infection. After adequate source control, long-course antibiotic therapy in critically ill post-operative patients is not associated with any clinical benefit. Although susceptible in the test, piperacillin-tazobactam can not replace carbapenems in patients with Escherichia coli and Klebsiella pneumoniae bloodstream infection that produce extended-spectrum beta-lactamase for definitive treatment. Deresuscitation of critically ill patients is associated with reduced mortality. Hydrocortisone therapy has potential role in the patients with septic shock and worth further evidence. The use of an energy-dense formulation for enteral delivery of nutrition can not improve 90-day survival rate in patients undergoing mechanical ventilation. Compared with early isocaloric parenteral nutrition, early enteral nutrition did not reduce mortality or the risk of secondary infections, but was associated with a greater risk of digestive complications in critically ill adults with septic shock.

Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial

Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE). Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7-14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21-25 days after randomisation). Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than -12·5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96). Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference -4·2% [95% CI -10·8 to 2·5]). In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference -0·7% [95% CI -7·9 to 6·4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related. Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens. AstraZeneca.

Correlation between cefepime utilisation and Pseudomonas aeruginosa resistance rates to β-lactams and carbapenems in patients with healthcare-associated infections.

There is direct link between overutilisation or abuse of antibiotics and Pseudomonas aeruginosa resistance rates, but other factors may also influence the resistance rate. This study aimed to observe changes in P. aeruginosa resistance rates in patients with hospital-acquired infections (HAIs) following a period of cefepime unavailability in an ICU. The study was designed as a retrospective observational analysis of trends in antibiotic utilisation and density of antibiotic resistance. It covered only P. aeruginosa isolates causing HAIs obtained from patients aged >18years. Isolates taken <48h after admission to the ICU and duplicate isolates were excluded. The effects of cefepime withdrawal from prescribing during the 2-year period on P. aeruginosa resistance density trends were also followed. During the study period (2009-2016), a total of 318 non-duplicate P. aeruginosa isolates causing HAIs in the ICU were collected. The predominant anatomical localisation of these infections (nearly 95%) was the lungs (pneumonia), surgical sites and urinary tract (69.18%, 18.24% and 6.92%, respectively). The isolates showed a lower resistance density (per/1000 PDs) in the last year (2016) compared with the first year of observation (2009) for all monitored antibiotics, with a peak in 2011. Although a decreasing trend of resistance density was recorded for all examined drugs, statistical significance was noted only for imipenem, meropenem and piperacillin/tazobactam (P<0.05) CONCLUSIONS: Temporary withdrawal of cefepime in a hospital resulted in a significant decrease in the density of P. aeruginosa isolates resistant to imipenem, meropenem, piperacillin/tazobactam, ceftazidime and cefepime.

Drug interaction between valproic acid and carbapenems in patients with epileptic seizures

Valproic acid (VPA) is a widely used antiepileptic drug (AED). When carbapenems are concomitantly used with VPA, the serum levels of VPA may decrease and aggravate seizures. The aim of this study was to evaluate the risk factors associated with decreased serum VPA levels and clinical outcome in patients being treated with a combination of carbapenems and VPA. Fifty-four adult patients who were treated with VPA for epileptic seizures concomitant with carbapenems for the treatment of infections were evaluated in this study. Serum VPA levels were measured before and during combination therapy with VPA and carbapenems, and the change in serum VPA levels was calculated. The risk factors related to the decrease in serum VPA levels and clinical outcomes were evaluated. Our results show that VPA concentrations were reduced to subtherapeutic levels after the introduction of carbapenems. The reduction in VPA concentrations was found within 24 hours of the start of treatment with carbapenems. VPA levels continuously declined while the combination of treatments was used, which aggravated epileptic seizures in 48% of the patients. Renal disease and enzyme-inducing AEDs were risk factors that contributed to the severity of reduced serum VPA levels during combined treatment with carbapenems. This study suggests that clinicians need to be aware of the reduction of VPA concentrations to subtherapeutic levels and the aggravation of seizures while patients are treated with a combination of carbapenems and VPA.

Mortality Impact of CLSI Carbapenem Breakpoint Changes in Enterobacteriaceae Bloodstream Infections: a Patient-level Analysis of Published Data

BackgroundIn 2010, the Clinical and Laboratory Standards Institute (CLSI) lowered susceptibility breakpoints for carbapenem agents, though few studies have evaluated the clinical impact of these changes. The objective of this study was to determine whether a clinical breakpoint exists for carbapenems in patients with Gram-negative Enterobacteriaceaebloodstream infections (GNBSIs).MethodsPatient-level data from 4 publications (Rhodes JN 2016, Biehle LR 2015, Patel TS 2015, Esterly JS 2012) reporting outcomes for GNBSIs treated with carbapenems for ≥48 hours were compiled. Patients with an MIC ≥16 mg/L to both imipenem (IMI) and meropenem (MER) were excluded. Classification and Regression Tree (CART) analyses were used to determine optimal splits for carbapenem MIC with respect to 30-day all-cause mortality. Univariate and multivariate regression analyses were conducted using Stata 14.ResultsA total of 194 patients were extracted. Klebsiella pneumoniae was the most common pathogen (70.1%) followed by Escherichia coli(15.0%). Primary bacteremia/unknown and urinary tract were the most common sources of GNBSI (31.4% and 25.8%, respectively). MER and IMI MICs were available for 144 patients (74.2%) and 138 patients (71.1%), respectively. Carbapenem agent used was known for 141 patients, of which 94 received MER, 24 received ertapenem, 12 received doripenem, and 11 received IMI. CART analysis identified a significant difference in mortality between patients infected with organisms having MER MICs ≤ 1 mg/L (n = 10/121, 8.3%) vs. those with >1 mg/L (n = 7/21, 33.3%; P <0.01) regardless of carbapenem used. This breakpoint was also identified in the subgroup of patients with available MER MICs who were treated with MER (n = 5/64, 7.8% vs. 7/19, 36.8%; P < 0.01). In multivariate logistic regression, MER MIC > 1 mg/L was associated with increased odds of 30-day mortality after controlling for ICU admission in the any carbapenem treatment (OR 5.0, 95% CI 1.63-15.6; P < 0.01) and MER treated populations (OR 7.16, 1.88-27.3; P < 0.01).ConclusionThis pooled patient-level analysis of GNBSIs treated with carbapenems represents the largest of its kind to date. A significant increase in mortality was identified in patients with MER non-susceptible isolates as defined by the 2010 CLSI breakpoints.Disclosures T. Patel, Merck: Grant Investigator, Research grant. J. Esterly, Merck: Employee, Salary. E. B. Hirsch, Merck: Grant Investigator, Grant recipient. The Medicines Company: Speaker’s Bureau, Speaker honorarium

Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study

Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of ceftazidime-avibactam compared with best available therapy in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens. REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18-90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Patients were randomised (1:1) to 5-21 days of treatment with either ceftazidime-avibactam (a combination of 2000 mg ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7-10 days after last infusion of study therapy, analysed in all patients who had at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643. Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 [91%; 95% CI 85·6-94·7] of 154 patients) and best available therapy (135 [91%; 85·9-95·0] of 148 patients). 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for ceftazidime-avibactam. These results provide evidence of the efficacy of ceftazidime-avibactam as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and P aeruginosa. AstraZeneca.

No Carbapenem Resistance in Pneumonia Caused by Klebsiella Species

Klebsiella species are a common cause of community- and nosocomial-acquired pneumonia. Antibiotic resistance to the class of carbapenem in patients with pneumonia caused by Klebsiella species is unusual. New studies report carbapenem resistance in patients with pneumonia caused by Klebsiella species.This article examines, retrospectively, antibiotic resistance in patients with community- and nosocomial-acquired pneumonia caused by Klebsiella species.The data of all patients with community- and nosocomial-acquired pneumonia caused by Klebsiella species were collected from the hospital charts at the HELIOS Clinic, Witten/Herdecke University, Wuppertal, Germany, within the study period 2004 to 2014. An antibiogram was created from all of the study patients with pneumonia caused by Klebsiella species. Sensitivity and resistance profiles were performed for the different antibiotics that have been consistently used in the treatment of patients with pneumonia caused by Klebsiella species. All demographic, clinical, and laboratory data of all of the patients with pneumonia caused by Klebsiella species were collected from the patients’ records.During the study period of January 1, 2004, to August 12, 2014, 149 patients were identified with community- and nosocomial-acquired pneumonia affected by Klebsiella species. These patients had a mean age of 70.6 ± 13 (107 [71.8%, 95% CI 64.6%–79%] men and 42 [28.2%, 95% CI 21%–35.4%] women). In all of the patients with pneumonia caused by Klebsiella species, there was resistance to ampicillin (P < 0.0001). Many patients with pneumonia caused by Klebsiella species (75.3%) also showed resistance to piperacillin (P < 0.0001). However, no patients with pneumonia caused by Klebsiella species showed resistance to imipenem or meropenem (P < 0.0001).Antibiotic resistance to the antibiotic class of carbapenem was not detected in patients with pneumonia caused by Klebsiella species.

Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins

Studies performed on samples larger than 100 subjects with a documented IgE-mediated hypersensitivity to penicillins have demonstrated a cross-reactivity rate of approximately 1% between penicillins and both imipenem and meropenem, whereas a single study found a cross-reactivity rate of 6.2% with aztreonam in 16 such subjects. To assess the cross-reactivity and tolerability of aztreonam and 3 carbapenems (imipenem-cilastatin, meropenem, and ertapenem) in patients with documented IgE-mediated hypersensitivity to penicillins. A total of 212 consecutive subjects with immediate reactions to penicillins and positive results on skin tests to at least 1 penicillin reagent underwent skin tests with aztreonam and carbapenems; subjects with negative results were challenged with escalating doses of aztreonam and carbapenems. All subjects displayed negative skin test results to both aztreonam and carbapenems; 211 accepted challenges and tolerated them. Challenges were not followed by full therapeutic courses. These data indicate the tolerability of both aztreonam and carbapenems in penicillin-allergic subjects. In those who especially require these alternative β-lactams, however, we recommend pretreatment skin tests, both because rare cases of cross-reactivity have been reported and because negative results indicate tolerability.

746Tolerability of Cephalosporins and Carbapenems in Patients with Reported Penicillin Allergies in a Real World Setting

746Tolerability of Cephalosporins and Carbapenems in Patients with Reported Penicillin Allergies in a Real World Setting