Ceftazidima/avibactam frente a otros antimicrobianos para el tratamiento de bacteriemias por Enterobacterales productores de carbapenemasa KPC: datos de la vida real en un hospital universitario de Argentina / Ceftazidime/avibactam versus other antibiotics for the treatment of KPC carbapenemase-producing Enterobacterales bacteremia: real-life data from a university hospital in Argentina

INTRODUCCIÓN: Las bacteriemias por Enterobacterales productores de carbapenemasa KPC (EPC-KPC) presentan una mortalidad elevada y opciones terapéuticas limitadas. OBJETIVOS: Describir y comparar la evolución de los pacientes con bacteriemia por EPC-KPC tratados con ceftazidima/avibactam (CA) frente a otros antimicrobianos (OA). PACIENTES Y MÉTODOS: Estudio prospectivo y retrospectivo de casos y controles. Se incluyeron pacientes adultos con bacteriemia por EPC-KPC, con una proporción entre casos tratados con CA y controles tratados con OA. de 1:2. Se analizaron variables clínicas, epidemiológicas y de evolución. RESULTADOS: Se incluyeron 48 pacientes (16 CA y 32 OA). Los casos se encontraban más frecuentemente neutropénicos (50 vs.16%, p = 0,012); asimismo, presentaron medianas de score de APACHE II más altas y de score de Pitt más bajas. El 65% de la cohorte total presentó un foco clínico y Klebsiellapneumoniae fue el microorganismo más frecuentemente aislado. Los casos recibieron una mayor proporción de tratamiento antimicrobiano empírico adecuado (81 vs. 53%, p = 0,05). La antibioterapia dirigida en casos y controles fue combinada en 38 y 91%, p = 0,009. Los casos presentaron menor mortalidad al día 7 y al día 30 relacionada a infección (0 vs. 22%, p = 0,04 y 0 vs. 34%, p = 0,008). Solo los controles desarrollaron shock, ingresaron a la unidad de cuidados intensivos y presentaron bacteriemia de brecha. CONCLUSIÓN: CA mostró beneficio clínico frente a OA para el tratamiento de pacientes con bacteriemia por EPC-KPC.

BACKGROUND: KPC-producing Enterobacterales bacteremia (KPCCPE) is associated with a high mortality rate and limited therapeutic options. AIM: To describe and compare the outcome of patients with KPC-CPE bacteremia treated with ceftazidime/avibactam (CA) versus other antibiotics (OA). METHODS: Prospective and retrospective cases and control study performed in adult patients with KPC-CPE bacteremia, with a 1:2 ratio between cases treated with CA. and controls treated with OA. Clinical, epidemiological, and outcome variables were analyzed. RESULTS: Forty-eight patients (16 CA and 32 OA) were included. Cases were more frequently neutropenic (50 vs. 16%, p = 0.012), presented higher median APACHE II score and lower Pitt score. Of the total cohort, 65% had a clinical source, and Klebsiella pneumoniae was the most frequently isolated microorganism. Cases received more adequate empirical antibiotic treatment (81 vs. 53%, p = 0.05). Targeted antibiotic therapy in cases and controls was combined in 38 and 91%, p = 0.009. Cases had a lower 7-day mortality and 30-day infection-related mortality (0 vs. 22%, p = 0.04 and 0 vs. 34%, p = 0.008). Only controls developed shock, were admitted to the intensive care unit, and had breakthrough bacteremia. CONCLUSION: CA. showed clinical benefit over OA in the treatment of patients with EPC-KPC bacteremia.

Clinical and bacterial characteristics of Pseudomonas aeruginosa affecting the outcome of patients with bacteraemic pneumonia.

Few studies have assessed the clinical and bacterial characteristics of Pseudomonas aeruginosa (PA) bacteraemic pneumonia (BP) episodes. This study analysed all non-duplicate PA-BP episodes from a tertiary hospital in 2013-2017. Epidemiology, clinical data, antimicrobial therapy and outcomes were recorded. Whole-genome sequencing was performed on PA blood isolates. The impact on early and late overall mortality of host, antimicrobial treatment and pathogen factors was assessed by multivariate logistic regression analysis. Of 55 PA-BP episodes, 32 (58.2%) were caused by extensively drug-resistant (XDR) PA. ST175 (32.7%) and ST235 (25.5%) were the most frequent high-risk clones. ß-Lactamases/carbapenemases were detected in 29 isolates, including blaVIM-2 (27.2%) and blaGES type (25.5%) [blaGES-5 (20.0%), blaGES-1 (3.6%) and blaGES-20 (1.8%)]. The most prevalent O-antigen serotypes were O4 (34.5%) and O11 (30.9%). Overall, an extensive virulome was identified in all isolates. Early mortality (56.4%) was independently associated with severe neutropenia (aOR = 4.64, 95% CI 1.11-19.33; P = 0.035) and inappropriate empirical antimicrobial therapy (aOR = 5.71, 95% CI 1.41-22.98; P = 0.014). Additionally, late mortality (67.3%) was influenced by septic shock (aOR = 8.85, 95% CI 2.00-39.16; P = 0.004) and XDR phenotype (aOR = 5.46, 95% CI 1.25-23.85; P = 0.024). Moreover, specific genetic backgrounds [ST235, blaGES, gyrA (T83I), parC (S87L), exoU and O11 serotype] showed significant differences in patient outcomes. Our results confirm the high mortality associated with PA-BP. Besides relevant clinical characteristics and inappropriate empirical therapy, bacteria-specific genetics factors, such as XDR phenotype, adversely affect the outcome of PA-BP.

Clinical impact of cefepime breakpoint in patients with carbapenem-resistant Klebsiella pneumoniae bacteraemia.

The application of cefepime breakpoint for carbapenem-resistant Klebsiella pneumoniae (CRKP) bacteraemia has not been explored. Adult cases of monomicrobial bloodstream infection (BSI) caused by cefepime-susceptible [minimum inhibitory concentration (MIC) ≤8 mg/L] K. pneumoniae isolates with carbapenem resistance between 2010 and 2015 were reviewed. Patients treated with cefepime were compared with those treated by other active agents using a propensity score-matched analysis to assess therapeutic effectiveness. The primary endpoint was 30-day crude mortality. A total of 114 patients experienced cefepime-susceptible CRKP bacteraemia and 40 (35.1%) died during hospitalisation. A total of 33 patients (28.9%) received cefepime therapy. Fifteen patients (13.2%) had BSI due to carbapenemase-producing isolates, and 86.7% (13/15) of carbapenemase-producing isolates were classified as cefepime susceptible dose-dependent (SDD). In the multivariate logistic regression analysis, 30-day mortality was independently associated with the presence of a critical illness [adjusted odds ratio (aOR) = 12.89, 95% confidence interval (CI) 3.88-42.83; P < 0.001], pneumonia (aOR = 5.97, 95% CI 1.65-21.76; P = 0.007) and rapidly fatal underlying disease (aOR = 6.43, 95% CI 1.30-31.09; P = 0.02). In contrast, cefepime-based therapy (aOR = 0.03, 95% CI 0.003-0.38; P = 0.006) and combination therapy (aOR = 0.09, 95% CI 0.02-0.36; P = 0.001) were protective against a fatal outcome. Based on current breakpoints for Enterobacterales, cefepime therapy was not associated with an unfavourable outcome for CRKP BSI with MIC-based dosing strategies. However, the susceptibility result of SDD to cefepime should alert clinicians for possible therapeutic failure.

Treatment of Bacteremia Caused by Enterobacter spp.: Should the Potential for AmpC Induction Dictate Therapy? A Retrospective Study.

Objective: Carbapenems are considered treatment of choice for bacteremia caused by potential AmpC-producing bacteria, including Enterobacter spp. We aimed to compare mortality following carbapenem vs. alternative antibiotics for the treatment of Enterobacter spp. bacteremia. Patients and Methods: We conducted a retrospective study in two centers in Israel. We included hospitalized patients with Enterobacter bacteremia treated with third-generation cephalosporins (3GC), piperacillin/tazobactam, quinolones, or carbapenem monotherapy as the main antibiotic in the first week of treatment, between 2010 and 2017. Cefepime was excluded due to nonavailability during study years. The primary outcome was 30-day all-cause mortality. Univariate and multivariate analyses were conducted, introducing the main antibiotic as an independent variable. Results: Two hundred seventy-seven consecutive patients were included in the analyses. Of these, 73 were treated with 3GC, 39 with piperacillin/tazobactam, 104 with quinolones, and 61 with carbapenems. All-cause 30-day mortality was 16% (45 patients). The type of antibiotics was not significantly associated with mortality on univariate or multivariate analyses. With carbapenems as reference, adjusted odds ratios (ORs) for mortality were 0.708, 95% confidence interval (CI) 0.231-2.176 with 3GC; OR 1.172, 95% CI 0.388-3.537 with piperacillin/tazobactam; and OR 0.586, 95% CI 0.229-1.4 with quinolones. The main antibiotic was not associated with repeated growth of Entrobacter spp. in blood cultures or other clinical specimens. Resistance development was observed with 3GC and piperacillin/tazobactam. Conclusions: Carbapenem treatment was not advantageous to alternative antibiotics, including 3GC, among patients with Enterobacter spp. bacteremia in an observational study.

Multidrug resistant and extensively drug resistant Acinetobacter baumannii hospital infection associated with high mortality: a retrospective study in the pediatric intensive care unit.

BACKGROUND: Multidrug resistant (MDR) and extensively drug resistant (XDR) Acinetobacter baumannii presents challenges for clinical treatment and causes high mortality in children. We aimed to assess the risk factors and overall mortality for MDR/XDR Acinetobacter baumannii infected pediatric patients. METHODS: This retrospective study included 102 pediatric patients who developed MDR/XDR Acinetobacter baumannii infection in the pediatric intensive care unit (PICU) of Shanghai Children's Hospital in China from December 2014 to May 2018. Acinetobacter baumannii clinical isolates were recovered from different specimens including blood, sputum, bronchoalveolar lavage fluid, cerebrospinal fluid, ascites, hydrothorax, and urine. Antibiotic susceptibility test was determined according to the Clinical and Laboratory Standards Institute interpretive criteria. Clinical and biological data were obtained from the patients' medical records. RESULTS: 102 patients with Acinetobacter baumannii infection were enrolled. The median age was 36 (9.6, 98.8) months, and there were 63 male in the case group. The overall mortality rate was 29.4%, while the Acinetobacter baumannii-associated mortality rate was 16.7% (17/102, 12 bloodstream infections, 4 meningitis and 1 intra-abdominal infection). Bloodstream infections occurred in 28 patients (27.5%), and 10 patients (9.8%) among them had central line-associated bloodstream infections (6 central venous catheters, 2 PICCs, 1 venous infusion port and 1 arterial catheter). Cerebrospinal fluid (CSF) cultures were positive in 4(3.9%) patients. 14(13.7%) patients got positive cultures in ascites and hydrothorax. Lower respiratory isolates (56/102) accounted for 54.9% of all patients. Non-survival patients appeared to have a lower NK cell activity (6.2% ± 3.61% vs. 9.15% ± 6.21%, P = 0.029), higher CD4+ T cell ratio (39.67% ± 12.18% vs. 32.66% ± 11.44%, P = 0.039),and a higher serum level of interlukin-8 (IL-8, 15.25 (1.62, 47.22)pg/mL vs. 0.1 (0.1, 22.99)pg/mL, P = 0.01) when Acinetobacter baumannii infection developed. Multivariate logistic analysis indicated that high serum level of Cr (RR, 0.934, 95%CI, 0.890-0.981; P = 0.007) and high BUN/ALB level (RR, 107.893, 95%CI, 1.425-870.574; p = 0.005) were associated with high risk of mortality in MDR/XDR Acinetobacter baumannii infected patients. CONCLUSION: MDR/XDR Acinetobacter baumannii infection is a serious concern in pediatric patients with high mortality. Bloodstream and central nervous system infection accounted for high risk of death. Acute kidney injury is associated with high risk of mortality.

Effect of C-Reactive Protein-Guided Antibiotic Treatment Duration, 7-Day Treatment, or 14-Day Treatment on 30-Day Clinical Failure Rate in Patients With Uncomplicated Gram-Negative Bacteremia: A Randomized Clinical Trial.

Importance: Antibiotic overuse drives antibiotic resistance. Gram-negative bacteremia is a common infection that results in substantial antibiotic use. Objective: To compare the clinical effectiveness of C-reactive protein (CRP)-guided, 7-day, and 14-day antibiotic durations 30, 60, and 90 days after treatment initiation. Design, Setting, and Participants: Multicenter, noninferiority, point-of-care randomized clinical trial including adults hospitalized with gram-negative bacteremia conducted in 3 Swiss tertiary care hospitals between April 2017 and May 2019, with follow-up until August 2019. Patients and physicians were blinded between randomization and antibiotic discontinuation. Adults (aged ≥18 years) were eligible for randomization on day 5 (±1 d) of microbiologically efficacious therapy for fermenting, gram-negative bacteria in blood culture(s) if they were afebrile for 24 hours without evidence for complicated infection (eg, abscess) or severe immunosuppression. Intervention: Randomization in a 1:1:1 ratio to an individualized CRP-guided antibiotic treatment duration (discontinuation once CRP declined by 75% from peak; n = 170), fixed 7-day treatment duration (n = 169), or fixed 14-day treatment duration (n = 165). Main Outcomes and Measures: The primary outcome was the clinical failure rate at day 30, defined as the presence of at least 1 of the following, with a non-inferiority margin of 10%: recurrent bacteremia, local suppurative complication, distant complication (growth of the same organism causing the initial bacteremia), restarting gram-negative-directed antibiotic therapy due to clinical worsening suspected to be due to the initial organism, or death due to any cause. Secondary outcomes included the clinical failure rate on day 90 of follow-up. Results: Among 504 patients randomized (median [interquartile range] age, 79 [68-86] years; 306 of 503 [61%] were women), 493 (98%) completed 30-day follow-up and 448 (89%) completed 90-day follow-up. Median antibiotic duration in the CRP group was 7 (interquartile range, 6-10; range, 5-28) days; 34 of the 164 patients (21%) who completed the 30-day follow-up had protocol violations related to treatment assignment. The primary outcome occurred in 4 of 164 (2.4%) patients in the CRP group, 11 of 166 (6.6%) in the 7-day group, and 9 of 163 (5.5%) in the 14-day group (difference in CRP vs 14-day group, -3.1% [1-sided 97.5% CI, -∞ to 1.1]; P < .001; difference in 7-day vs 14-day group, 1.1% [1-sided 97.5% CI, -∞ to 6.3]; P < .001). By day 90, clinical failure occurred in 10 of 143 patients (7.0%) in the CRP group, 16 of 151 (10.6%) in the 7-day group, and 16 of 153 (10.5%) in the 14-day group. Conclusions and Relevance: Among adults with uncomplicated gram-negative bacteremia, 30-day rates of clinical failure for CRP-guided antibiotic treatment duration and fixed 7-day treatment were noninferior to fixed 14-day treatment. However, interpretation is limited by the large noninferiority margin compared with the low observed event rate, as well as low adherence and wide range of treatment durations in the CRP-guided group. Trial Registration: ClinicalTrials.gov Identifier: NCT03101072.

Paradoxical Antibiotic Effect of Ampicillin: Use of a Population Pharmacokinetic Model to Evaluate a Clinical Correlate of the Eagle Effect in Infants With Bacteremia.

BACKGROUND: High doses of ampicillin are often used to achieve therapeutic drug concentrations in infants. A paradoxical antibiotic effect, often called the Eagle effect, occurs when increasing concentrations of antibiotic above a threshold results in decreased efficacy. It is unknown if infants treated with ampicillin are at risk for this paradoxical effect. METHODS: We identified infants <28 days of age with Escherichia coli, Enterococcus or Streptococcus agalactiae (group B streptococcus) bloodstream infections from 1997 to 2012 and previously included in an ampicillin pharmacokinetic (PK) modeling study. We compared the odds of death for ampicillin dose, estimated time above the minimum inhibitory concentration (T > MIC) and PK parameters using separate logistic regression models. Adjusted logistic regression and Poisson models were used to calculate the odds of prolonged bacteremia ≥3 days and the duration of bacteremia, respectively, for dose, T > MIC and multiple PK parameters. RESULTS: Among 1272 infants meeting inclusion criteria, odds of death 7 or 30 days after the positive blood culture were not consistent with a paradoxical effect across any of the dosing regimens or PK parameters evaluated. The odds of prolonged bacteremia was lowest at the lowest dose category and the lowest daily dose category but not associated with the area-under-the-concentration time curve from 0 to 24 hours, or the maximum or minimum concentrations at steady state. T > MIC of ≥50% of the dosing interval was associated with decreased duration of bacteremia and odds of prolonged bacteremia. CONCLUSIONS: It is unlikely that a paradoxical antibiotic effect will have a clinical correlate when ampicillin is used for neonatal bacteremia. A T > MIC ≥50% decreased both duration of bacteremia and odds of prolonged bacteremia.

Multicentre study of risk factors for mortality in patients with Acinetobacter bacteraemia receiving colistin treatment.

Colistin remains a last-line antibiotic for the treatment of infections by multidrug-resistant Acinetobacter species. However, mortality rates are high in patients with Acinetobacter infection receiving colistin treatment. This multicentre study evaluated whether colistin susceptibility, additional antimicrobial agents or other prognostic factors influenced the clinical outcomes of patients receiving colistin treatment for Acinetobacter bacteraemia. This retrospective study enrolled 122 adults receiving colistin for monomicrobial Acinetobacter bacteraemia at six medical centres in the ACTION Study Group over an 8-year period. Clinical information, antimicrobial susceptibility and colistin resistance determinants were analysed. The primary outcome measure was 14-day mortality. Among 122 patients, 18 and 104 were infected with colistin-resistant (ColR) isolates [minimum inhibitory concentration (MIC) ≥4 mg/L] and colistin-susceptible (ColS) isolates (MIC ≤2 mg/L), respectively. Patients infected with ColR and ColS isolates did not differ significantly with regard to Charlson comorbidity index, invasive procedures, sources of bacteraemia, disease severity and 14-day mortality rate (44.4% vs. 34.6%; P = 0.592). No specific additional antimicrobial agent was independently associated with higher or lower mortality. Coronary artery disease, higher Acute Physiology and Chronic Health Evaluation (APACHE) II score and bacteraemia caused Acinetobacter baumannii were independent risk factors associated with 14-day mortality. Mechanisms of colistin resistance were associated with amino acid variants in the pmrCAB operon. Finally, previously unreported Acinetobacter nosocomialis amino acid variants related to colistin resistance were identified. In conclusion, colistin susceptibility and colistin combination antimicrobial treatment were not associated with decreased 14-day mortality in patients with Acinetobacter bacteraemia receiving colistin treatment.

Treatment Outcome of Bacteremia Due to Non-Carbapenemase-producing Carbapenem-Resistant Klebsiella pneumoniae Bacteremia: Role of Carbapenem Combination Therapy.

PURPOSE: Infections caused by carbapenemase-producing Klebsiella pneumoniae are emerging causes of morbidity and mortality worldwide. Optimal treatment for non-carbapenemase-producing carbapenem-resistant K pneumoniae (nCP-CRKP) bacteremia remains undefined. The goal of this study was to assess the clinical outcome, predictors of mortality, and therapeutic strategy of carbapenems for nCP-CRKP bacteremia. METHODS: A retrospective study of monomicrobial bacteremia caused by nCP-CRKP, at a medical center between 2010 and 2015 was conducted. CRKP which was defined as a minimum inhibitory concentration (MIC) of ≥ 2 for ertapenem or ≥ 4 mg/L for meropenem, or imipenem. Multiplex polymerase chain was applied to detect carbapenemase genes. The patients definitively treated with combination therapy were compared with monotherapy using a propensity score-matched analysis to assess therapeutic effectiveness. The primary end point was the 30-day crude mortality and clinical prognostic factors were assessed. FINDINGS: Overall 171 patients met criteria were eligible for the study and their overall 30-day mortality rate was 38.6%. The multivariate logistic regression analysis showed that combination therapy was associated with a lower 30-day mortality rate (adjusted odds ratio [aOR], 0.11; 95% CI, 0.03-0.43; P = 0.001) and less clinical (aOR, 0.21; 95% CI, 0.08-0.58; P = 0.003) and microbiologic (aOR, 0.36; 95% CI, 0.19-0.71; P = 0.003) failure. However, the 30-day mortality rate in the cases infected by a pathogen with a meropenem MIC ≤8 mg/L receiving carbapenem-containing or carbapenem-sparing combination regimens was similar (15 of 58 [25.9%] vs 5 of 20 [23.3%]; P = 1.0). IMPLICATIONS: Combination therapy, regardless of carbapenem-containing or carbapenem-sparing, with one or more active agents improved survival more than monotherapy and was more effective in patients with critical illness. (Clin Ther. 2020; 42:XXX-XXX) © 2020 Elsevier HS Journals, Inc.

Treatment and outcomes of Enterococcus faecium bloodstream infections in solid organ transplant recipients.

Optimal antimicrobial therapy for Enterococcus faecium bloodstream infection (EFBSI) in the solid organ transplant (SOT) population is not well defined. The purpose of this study was to describe the pharmacotherapy and outcomes of EFBSI in SOT patients. This was a single-center retrospective cohort of SOT patients with EFBSI from 2013 to 2019. Susceptibility testing was performed with Vitek® 2 or Etest. Estimates of optimal DAP pharmacokinetic/pharmacodynamic exposures (dose <10 mg/kg, fAUC/MIC >27.4) were made from previously established literature and equations. Fifty-one unique cases were included in the analysis. The median age was 61 years and liver (64%), intestinal (19%), and kidney (12%) were the most common organs transplanted. Most patients had indwelling central lines (75%) at the time of bacteremia; intra-abdominal abscesses/fluid collections were present in 44% of patients and 8% had endocarditis. Nineteen (37%) patients had polymicrobial infections. The most common definitive antimicrobial regimens were as follows: DAP plus beta-lactam (46%), DAP monotherapy (18%), and LZD (25%). Of the 33 patients that received DAP, 21% of E faecium isolates developed DAP resistance. 30-day mortality was 25% overall but higher in patients who received an initial DAP dose <10 mg/kg (43% vs 13%). Vancomycin-resistance, severity of illness, neutropenia, and source control were also associated with mortality. Inadequate DAP dosing for EFBSI may be associated with mortality in the SOT population. Larger, controlled analyses are necessary to determine the impact of optimized pharmacodynamics in this population.

Advances in the therapy of bacterial bloodstream infections.

BACKGROUND: Advances in the diagnostic and therapeutic management of patients with bloodstream infections (BSIs) have been achieved in the last years, improving clinical outcome. However, mortality associated with some pathogens, such as Staphylococcus aureus and Enterococcus spp., is still high. In addition, the spread of antibiotic resistance, mainly among Gram-negative bacteria, reduces treatment options in some circumstances. Therefore, interest in new drugs, combination regimens and optimal dosing schedules is rising. OBJECTIVES: Our aim is to summarize the current evidence on available antibiotic regimens for patients with bacterial BSI, focusing on drug choice, combination regimens and optimal dosing schedules. We selected bacteria that are difficult to manage because of virulence factors (i.e. methicillin-susceptible S. aureus), tolerance to antibiotic activity (i.e. Enterococcus faecalis), and/or susceptibility patterns (i.e. methicillin-resistant S. aureus, vancomycin-resistant enterococci, carbapenem-resistant Enterobacteriaceae, multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii). SOURCES: MEDLINE search with English language and publication in the last 5 years as limits. CONTENT AND IMPLICATIONS: The literature gaps on the use of new drugs, the uncertainties regarding the use of combination regimens, and the need to optimize dosing schedules in some circumstances (e.g. augmented renal clearance, renal replacement therapy, high inoculum BSI sources, and isolation of bacteria showing high MICs) have been revised.

Assessment of mortality stratified by meropenem minimum inhibitory concentration in patients with Enterobacteriaceae bacteraemia: A patient-level analysis of published data.

In 2010, the Clinical and Laboratory Standards Institute (CLSI) lowered carbapenem breakpoints to reduce the proportion of 'susceptible' organisms that produced carbapenemases. Few studies have evaluated the effect of this change on clinical outcomes. This systematic review aimed to evaluate the effect of carbapenem MICs on 30-day mortality from pooled patient-level data from studies of patients treated with carbapenems across a range of meropenem MICs. PubMed was searched to March 2019 with the terms 'carbapenem', 'meropenem', 'imipenem', 'doripenem', 'ertapenem', 'susceptibility' and 'outcomes'. Studies were included in the analysis if patients had Enterobacteriaceae bacteraemia treated with a carbapenem for ≥48 h and mortality was reported. Studies were excluded if all isolates were either susceptible or resistant to meropenem based on CLSI 2010 breakpoints or if only carbapenemase-producing isolates were included. Authors were contacted for patient-level data. The primary outcome was 30-day mortality, with planned subset analyses of patients treated with meropenem, receiving active combination therapy, treated in the ICU or infected with Klebsiella pneumoniae. Of 157 articles identified, 4 met the inclusion criteria (115 eligible patients). The odds of mortality increased with each increasing meropenem MIC dilution (OR = 1.51, 95% CI 1.06-2.15) as a continuous variable. A similar increase in odds was observed in patients treated with meropenem, treated in the ICU, infected with K. pneumoniae or receiving no other active antimicrobials. Increasing meropenem MICs in Enterobacteriaceae were associated with increased mortality; however, more work is needed to define optimal clinical decision rules for infections within the susceptible range.

Timing, distribution, and microbiology of infectious complications after necrotizing pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a common acute abdominal disease worldwide, and its incidence rate has increased annually. Approximately 20% of AP patients develop into necrotizing pancreatitis (NP), and 40% to 70% of NP patients have infectious complications, which usually indicate a worse prognosis. Infection is an important sign of complications in NP patients. AIM: To investigate the difference in infection time, infection site, and infectious strain in NP patients with infectious complications. METHODS: The clinical data of AP patients visiting the Department of General Surgery of Xuanwu Hospital of Capital Medical University from January 1, 2014 to December 31, 2018 were collected retrospectively. Enhanced computerized tomography or magnetic resonance imaging findings in patients with NP were included in the study. Statistical analysis of infectious bacteria, infection site, and infection time in NP patients with infectious complications was performed, because knowledge about pathogens and their antibiotic susceptibility patterns is essential for selecting an appropriate antibiotic. In addition, the factors that might influence the prognosis of patients were analyzed. RESULTS: In this study, 539 strains of pathogenic bacteria were isolated from 162 patients with NP infection, including 212 strains from pancreatic infections and 327 strains from extrapancreatic infections. Gram-negative bacteria were the main infectious species, the most common of which were Escherichia coli and Pseudomonas aeruginosa. The extrapancreatic infection time (9.1 ± 8.8 d) was earlier than the pancreatic infection time (13.9 ± 12.3 d). Among NP patients with early extrapancreatic infection (< 14 d), bacteremia (25.12%) and respiratory tract infection (21.26%) were predominant. Among NP patients with late extrapancreatic infection (> 14 d), bacteremia (15.94%), respiratory tract infection (7.74%), and urinary tract infection (7.71%) were predominant. Drug sensitivity analysis showed that P. aeruginosa was sensitive to enzymatic penicillins, third- and fourth-generation cephalosporins, and carbapenems. Acinetobacter baumannii and Klebsiella pneumoniae were sensitive only to tigecycline; Staphylococcus epidermidis and Enterococcus faecium were highly sensitive to linezolid, tigecycline, and vancomycin. CONCLUSION: In this study, we identified the timing, the common species, and site of infection in patients with NP.

[The efficacy and safety of different antimicrobial regimens in carbapenem-resistant Klebsiella pneumoniae bloodstream infections].

Objective: To evaluate the efficacy and safety of different antimicrobial regimens in patients with bloodstream infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). Methods: The clinical date of patients with CRKP bloodstream infections were retrospectively analyzed at the First Affiliated Hospital of Zhejiang University Medical College between January 2017 and January 2018. All subjects were separated into three groups based on antibiotics regimens over 72 hours, including meropenem 2.0 g every 8 hours, tigecycline 200 mg as initial dose and 100 mg every 12 hours, and polymyxin B 1.25 mg/kg every 12 hours as salvage treatment of tigecycline. Results: A total of 86 patients were finally recruited, including 14, 52 and 20 patients in groups of meropenem, tigecycline and polymyxin B salvage, respectively. All of the strains were resistant to meropenem and susceptible to tigecycline and polymyxin B initially, while 2 of them became resistant to tigecycline during treatment. The 28-day mortality was significantly higher in meropenem group (13/14) than that in tigecycline group and polymyxin B salvage group (61.5%, 32/52) and (12/20), respectively (P<0.01), while as no significant difference was seen in the last two groups (χ(2)=0.014, P>0.05). The incidences of hepatic impairment [3.8%(2/52) vs. 1/20] and renal dysfunction (0 vs. 1/20) between tigecycline group and polymyxin B salvage group were both comparable (P>0.05). Conclusion: The meropenem-based therapy is not recommended for CRKP-related bloodstream infections. Tigecycline-based therapy is still disappointing despite salvage use of polymyxin B after 72 hours. Hepatic and nephretic toxicities caused by additional polymyxin B are acceptable.

Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Enterobacteriales Coresistant to Carbapenems and Polymyxins.

In this article, we report a case series of patients with infections caused by Enterobacteriales coresistant to carbapenems and polymyxins who were treated with ceftazidime/avibactam (CAZ-AVI) salvage therapy on a compassionate-use protocol. We enrolled 29 adult patients in 3 centers that had an infection due to a resistant microorganism and for whom the treatments available were considered ineffective, treated them with CAZ-AVI, and assessed clinical and microbiological cure at the end of treatment and all-cause mortality at 14 days and 30 days. The antimicrobial susceptibility profile was determined using broth microdilution, and total genomic DNA was sequenced. Twelve (41.4%) patients had bacteremia, and 48.3% (14/29) of the infections were treated with combination therapy. All strains were producers of KPC-2 and were susceptible to CAZ-AVI (MIC90, 1 µg/ml). Clinical success was high (24/29 [82.7%; 95% confidence interval, 64.2 to 94.2%]), even for the bacteremic cases (75%). The 14-day and 30-day mortality rates were 9/29 (31%) and 15/29 (51.7%), respectively. The 14-day mortality rate for pneumonia was the same as that for bloodstream infections (33.3%) and although not significant, we found that patients with renal impairment that received adjusted doses of CAZ-AVI had high mortality (4/9 [44%]; P = 0.22). We concluded that CAZ-AVI is an option for the treatment of severe infections due to difficult-to-treat drug-resistant Enterobacteriales.

The intervention by an antimicrobial stewardship team can improve clinical and microbiological outcomes of resistant gram-negative bacteria.

Antibiotic stewardship (AS) improves patient outcomes and rates of antibiotic susceptibilities. However, the long-term effect of AS programs (ASPs) on mortality is unclear. This study aimed to assess the impact of bedside interventions by an AS team (AST) on clinical and microbiological outcomes. This retrospective study enrolled patients with bloodstream infections (BSI) and long-term use of broad-spectrum antibiotics (more than 7 days). The main outcomes were 30-day and in-hospital mortality of patients with BSI. The secondary outcomes were the day of therapy (DOT) and susceptibility of antipseudomonal agents. Cases were classified into two groups: the pre-ASP group comprised cases between 2011 and 2013 and the post-ASP group, between 2014 and 2016. The outcomes were then compared between the two groups. Among the patients with all BSI (n = 1187), no significant differences in 30-day mortality were observed between those in the pre-ASP and post-ASP groups. However, in-hospital mortality was significantly lower in the post-ASP group than that in the pre-ASP group (24.8% vs. 18.0%; P = 0.004). Furthermore, the 30-day and in-hospital mortality of resistant gram-negative bacteraemia was significantly lower (20.4% vs.10.5%; P = 0.04 and 28.0% vs.16.1%; P = 0.03). The DOT of broad-spectrum antibiotics decreased except that of tazobactam/piperacillin. The susceptibilities of tazobactam/piperacillin, ceftazidime, cefepime, sulbactam/cefoperazone, gentamicin, ciprofloxacin levofloxacin, imipenem and meropenem were significantly better. Interventions by the AST can improve the clinical and microbiological outcomes, especially resistant gram-negative bacteria. Furthermore, this effect of our ASP can continue for a long term.

Risk Factors for Mortality in Children with Acinetobacter baumannii Bacteremia in South Korea: The Role of Carbapenem Resistance.

Aims: Acinetobacter baumannii has become an important nosocomial pathogen that causes invasive infections. We conducted a retrospective study to evaluate the risk factors for mortality due to A. baumannii bacteremia in children. Materials and Methods: We reviewed data from Seoul National University Children's Hospital from 2002 to 2013 for children with A. baumannii bacteremia, including age, gender, underlying disease, associated site of infection, duration of hospitalization, presence of neutropenia, and antibiotic susceptibility data. The outcome measures were the 7- and 30-day mortality rates. Results: Among 74 A. baumannii bacteremia cases, 35.1% were carbapenem nonsusceptible. Common comorbidities were malignancy or hematologic diseases (28.4%), followed by gastrointestinal/hepatobiliary diseases (21.6%). A total of 47.3% of patients had isolated bacteremia, and in 33.8% of patients, pneumonia accompanied bacteremia. The mortality rates were 18.9% at 7 days and 35.1% at 30 days. The significant associated factors for 30-day mortality were carbapenem nonsusceptibility (adjusted hazard ratio [aHR]: 1.28, 95% confidence interval [CI]: 1.10-11.82, p = 0.034), neutropenia (aHR: 1.68, 95% CI: 1.60-18.03, p = 0.007), and prior intensive care unit (ICU) admission (aHR: 1.15, 95% CI: 1.03-9.73, p = 0.045). The mortality rate among neutropenic patients with inappropriate empirical antibiotics was higher than that among patients with appropriate empirical antibiotics (90.1% vs. 33.3%, p = 0.031). Conclusions: We identified carbapenem nonsusceptibility, neutropenia, and prolonged ICU stay as independent risk factors for mortality due to A. baumannii bacteremia in children. An early administration of appropriate antibiotics should be enacted, especially in patients with neutropenia.

Prevalence and 30-day all-cause mortality of carbapenem-and colistin-resistant bacteraemia caused by Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae: Description of a decade-long trend.

BACKGROUND: Bacteraemia due to carbapenem-resistant gram-negative bacteria is challenging. This study examined the burden of carbapenem and colistin resistance in Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii bacteraemia in Oman. METHODS: Adult patients admitted to Sultan Qaboos University Hospital between January 1, 2007 and December 31, 2016 with positive blood cultures for P. aeruginosa, A. baumannii, or K. pneumoniae were identified. Rates of carbapenem resistance, trends in prevalence, and 30-day all-cause mortality were examined. RESULTS: Two hundred and twenty-seven (29.8%) of 761 bacteraemia cases due to these three isolates were carbapenem-resistant, with 87.2% being healthcare-associated. A. baumannii caused 52% of all carbapenem-resistant bacteraemia, K. pneumoniae caused 30%, and P. aeruginosa caused 18%. Rates of carbapenem resistance in P. aeruginosa, A. baumannii, and K. pneumoniae bacteraemia increased from 20%, 67%, and 0%, respectively, in 2007 to 25%, 86%, and 35%, respectively, in 2016. Seventeen (7.9%) carbapenem-resistant bacteraemia cases were also colistin-resistant. Thirty-day all-cause mortality was 62% in patients with carbapenem-resistant bacteraemia and 22% in patients with carbapenem-sensitive bacteraemia. CONCLUSIONS: The prevalence of carbapenem-resistant K. pneumoniae, A. baumannii, and P. aeruginosa bacteraemia is increasing alarmingly in Oman, with a large proportion of K. pneumoniae and P. aeruginosa demonstrating additional resistance to colistin. Patients with carbapenem-resistant bacteraemia had higher 30-day all-cause mortality.

A retrospective analysis of Pseudomonas aeruginosa bloodstream infections: prevalence, risk factors, and outcome in carbapenem-susceptible and -non-susceptible infections.

Background: Pseudomonas aeruginosa (PA) is a leading cause of nosocomial infections, and carbapenem non-susceptible strains are a major threat to patient safety. Methods: A single center, retrospective comparative analysis of carbapenem-non-susceptible PA (CnSPA) and carbapenem-susceptible PA (CSPA) bloodstream infections (BSIs) was conducted between January 1, 2007, and December 31, 2016. Prevalence and risk factors associated with CnSPA BSIs were examined. Results: The study enrolled 340 patients with PA BSIs; 30.0% (N = 101) of patients had CnSPA. High APACHE II scores (≥15), central venous catheterization, and delayed application of appropriate definitive therapy were independently associated with higher risk of mortality in PA BSIs. Multivariate analysis revealed that respiratory disease and exposure to carbapenems within the previous 90 days to onset of BSI were independent risk factors for acquisition of CnSPA BSIs. Overall all-cause 30-day mortality associated with PA BSIs was 26.8% (91/340). In addition, mortality was higher in patients with CnSPA than in those with CSPA (37.6% vs. 22.2%, respectively; P = 0.003). Corticosteroid therapy and delayed receipt of effective definitive therapy were independent risk factors for death from CnSPA BSIs. Conclusion: Increased incidence of CnSPA BSIs was observed during the study period, with higher mortality seen in patients with these infections. Respiratory disease and exposure to carbapenems were independent risk factors for development of CnSPA BSIs. Appropriate definitive therapy reduced mortality rates. BLBLIs were as effective as carbapenems as a treatment for PA BSIs.