Carbapenem-resistant Gram-negative Research Articles

Gram-negative bacteremia, the risk factors, and outcome in children

We aimed to determine the epidemiology and resistance patterns of Gram-negative bacteria, the risk factors and outcome of bloodstream infection (BSI). In all, 412 episodes in children who were hospitalized with the diagnosis of bacteremia were analyzed. The most common microorganisms were Klebsiella spp. (43.9%), Escherichia coli (13.5 %) and Acinetobacter spp. (10.6 %). Among isolates, 41.2 % were multidrug-resistant, 13.5 % were extensively drug-resistant and 0.4 % were pan-drug-resistant. Carbapenem resistance was revealed in 27.6 % of isolates. Carbapenem and colistin resistance increased over the years. The most common risk factors were the presence of a central-venous catheter and pediatric intensive care unit admission. Clinical response and infection-related mortality were significantly different in cases infected with carbapenem-resistant gram-negative (CRGN) vs carbapenem-susceptible gram-negative bacteria. The increase in multi-resistant Klebsiella spp. seems to be the biggest obstacles in fight against nosocomial infections. The increasing number of CRGN infections over the years affects both the clinical response and mortality rate of BSI.

Cross-contamination of carbapenem-resistant Gram-negative bacteria between patients and the hospital environment in the first year of a newly built surgical ward

BackgroundTransmission and outbreaks of carbapenem-resistant gram-negative (CRGN) bacteria in hospitals are often associated with contamination of the wastewater environment. We performed a prospective observational study to investigate the colonisation of the hospital wastewater environment during the first year of occupancy of the surgical intermediate and intensive care units of a newly constructed building at the University Hospital of Heidelberg, Germany. MethodsWe performed monthly screening of the wastewater system (toilets and sinks) for 12 months, starting one month before opening (1 October 2020 to 30 October 2021). Admission and weekly rectal screening of patients for CRGN were also performed in parallel. Bacterial isolates were characterised by whole genome sequencing. Results27 of 1978 (1.4%) admitted patients were colonised/infected with CRGN. A total of 29 CRGN isolates from 24 patients and 52 isolates were available for sequencing. Within the first month of occupancy, we identified seven patients colonised/infected with CRGN, while none were found in the environmental reservoirs. The first detection of CRGN isolates in the sewage system started five months after the first occupancy. Two previously non-colonised patients were colonised/infected with Pseudomonas aeruginosa strains colonising the sewage system. The significant identity of plasmids carrying the carbapenemase gene suggests that long-term colonisation of the sewage system facilitates the emergence of new carbapenem-resistant clones. InterpretationCross-contamination between patients and the hospital environment is bidirectional. Our study demonstrated that contamination of the hospital wastewater environment may lead to persistent colonisation and may serve as a reservoir for nosocomial acquisition of CRGN.

EFFICACY AND SAFETY OF USING COLISTIN IN NEONATES : A SYSTEMATIC REVIEW

Colistin is a cationic polypeptide antibiotic that belongs to the family of polymyxins and kills bacteria by interfering with the functioning of the bacterial cell. When given intravenously, colistin has the potential to cause a number of potentially harmful side effects, the most prevalent of which is nephrotoxicity. Recent studies have shown that patients who receive therapy with intravenous colistin run a risk of developing decreased kidney function ranging from 7.5% to 18.6% of the time. This risk is higher in patients who are older. However, it is essential to keep in mind that treatment with intravenous colistin, in the same way as treatment with other nephrotoxic drugs can result in conditions such as infection, septic shock, and the failure of several organs, it is vital to keep in mind that treatment with intravenous colistin. The bactericidal actions of colistin are demonstrated to be effective against a significant proportion of Gram-negative aerobic bacilli. It wasn't until the 1950s that it was first used in the United States, but by the 1980s, intravenous versions of the drug had been phased out due to the nephrotoxicity they caused. However, due to a rise in the incidence of illnesses caused by carbapenem-resistant Gram-negative (CRGN) bacteria and a dearth of newly developed antimicrobial drugs that are active against multidrug-resistant Gram-negative germs, the effectiveness of colistin has been called into question once again. The effectiveness of colistin in newborns might range anywhere from 50 to 98 percent. In this particular research endeavor, hyponatremia was identified as a potential adverse impact.

Outcome, risk factors and therapeutic strategies in carbapenem-resistant Gram-negative bacteraemia from Pakistan.

Carbapenem-resistant Gram-negative (CRGN) bacteraemia has high mortality and limited therapeutic options. We assessed the risk factors and outcome of CRGN bacteraemia treated with limited options. A prospective cohort study done at a tertiary care hospital in Pakistan, from October 2021 to August 2022. All patients >18 years with CRGN bacteraemia were assessed for demographics, source, risk factors and treatment received. Outcome was assessed as bacterial clearance and all-cause mortality at Day 14 of bacteraemia. We included 175 patients. Median age was 45 years (IQR 30-58) and the majority of our patients were on haemodialysis (75%). We found 14 day mortality in 26.8% of our patients; in addition, microbiological clearance was achieved in 95%. The central line (49.7%) was the most common source and Klebsiella spp. (47%) the most common organism. On multivariate analysis, risk factors for mortality were Foley's catheter [aOR 2.7 (95% CI 1.1-6.5)], mechanical ventilation [aOR 5.1 (95% CI 1.6-15.8)] and Pitt bacteraemia score >4 [aOR 3.48 (95% CI 1.1-10.5)]. Source control was a significant protective factor [aOR 0.251 (95% CI 0.09-0.6)]. The majority received a colistin-based regimen with no difference in mortality between monotherapy and combination therapy. Our cohort of CRGN bacteraemia is unique, comprising younger patients mostly on haemodialysis with a central line as the source of bacteraemia and we have found 14 day mortality of 27%. Colistin with various combinations can be an effective option in patients with renal failure having prompt source control.

Prevalence of bloodstream infection pathogens in hemato-oncological patients and predictors of carbapenem-resistant gram-negative bacterial infections during febrile neutropenia.

Carbapenem-Resistant Gram-Negative (CRGN) Bloodstream Infections (BSI) represent a therapeutic challenge, especially in the context of Febrile Neutropenia (FN) in cancer patients. We characterized pathogens causing BSI in patients aged ≥18 years who had undergone systemic chemotherapy for solid or hematological cancers between 2012 and 2021 in Porto Alegre, Brazil. Predictors of CRGN were evaluated through a case-control analysis. Each case was matched to two controls from whom CRGN were not isolated and had the same sex and year of inclusion in the study. From 6094 blood cultures evaluated, 1512 (24.8%) showed positive results. Gram-negative bacteria accounted for 537 (35.5%) of the isolated bacteria, of which 93 (17.3%) were carbapenem-resistant. From 105 patients included in the case-control analysis, all cases had baseline hematological malignancies (60% acute myeloid leukemia). Variables related to CRGN BSI in Cox regression analysis were the first chemotherapy session (p<0.01), chemotherapy performed in the hospital setting (p=0.03), intensive care unit admission (p<0.01), and CRGN isolation in the previous year (p<0.01). Patients with CRGN BSI received 75% less empirical active antibiotics and had 27.2% higher 30-day mortality rates than controls. A CRGN risk-guided approach should be considered for empirical antibiotic therapy in patients with FN.

618. Pharmacokinetic/pharmacodynamic analysis of combination therapy with continuous infusion (CI) fosfomycin plus extended-infusion (EI) or CI beta-lactams for treating documented carbapenem-resistant Gram-negative bloodstream infections and/or hospital-acquired pneumonia: a case series

Abstract Background To describe the pharmacokinetic/pharmacodynamic (PK/PD) behaviour and the microbiological outcome of combination therapy with continuous infusion (CI) fosfomycin plus extended-infusion (EI) or CI beta-lactams for treating severe carbapenem-resistant Gram-negative (CR-GN) infections. Methods Single-center retrospective study of patients who were treated with CI fosfomycin plus EI or CI beta-lactams for severe CR-GN infections and who underwent therapeutic drug monitoring (TDM), from 01 April 2021 to 31 January 2022. Concentrations of CI fosfomycin, meropenem and ceftazidime-avibactam were determined at steady-state (Css), while those of EI cefiderocol were measured at trough (Cmin). The desired joint PK/PD targets of combination therapy were considered as optimal when simultaneously the area-under-the curve to minimum inhibitory concentration (AUC/MIC) ratio for fosfomycin was &amp;gt; 83 and the Css/MIC for meropenem or for ceftazidime-avibactam or the Cmin/MIC ratio for cefiderocol was &amp;gt; 4 (quasi-optimal if only one of the two was achieved, and suboptimal if none of the two was achieved). Relationship between the joint PK/PD targets and microbiological failure (MF) defined as isolation of the same pathogens from follow-up blood cultures or BAL and assessed within 30 days of treatment onset, was investigated. Results Among the 16 retrieved patients with documented CR-GN infections, 12 underwent TDM of both fosfomycin and beta-lactams, and seven out of these (3 HAP, 3 BSI+HAP, and one BSI) had determination of fosfomycin MIC determined by agar-dilution (see Table). The joint PK/PD targets were optimal in 4 cases and quasi-optimal in the other 3y. MF occurred in two patients (29%) who were affected by HAP, received combination therapy with ceftazidime-avibactam, and achieved only quasi-optimal joint PK/PD targets (with fosfomycin AUC/MIC &amp;lt; 83). No MF occurred in patients with optimal joint PK/PD targets. Summary of the relationship between PK/PD targets and microbiological failure in patients receiving combination therapy with CI fosfomycin plus EI/CI beta-lactams Conclusion CI fosfomycin in combination with EI/CI beta-lactams may allow for the achievement of optimal joint PK/PD targets in most patients with CR-GN infections, and may represent a potential strategy for minimizing the risk of MF. Disclosures All Authors: No reported disclosures.

A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative bloodstream infections and/or ventilator-associated pneumonia

ObjectivesTo describe the pharmacokinetic/pharmacodynamic (PK/PD) behaviour of continuous infusion (CI) ceftazidime-avibactam and the microbiological outcome in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative (CR-GN) bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP). MethodsCritically ill patients with different degrees of renal function who were treated with CI ceftazidime-avibactam for documented CR-GN infections, and who underwent therapeutic drug monitoring from April 2021 to March 2022, were retrospectively assessed. Ceftazidime and avibactam concentrations were determined at steady-state, and the free fraction (fCss) was calculated. The joint PK/PD target of ceftazidime-avibactam was considered as optimal when both Css/MIC ratio for ceftazidime ≥4 (equivalent to 100%fT>4xMIC) and Css/CT ratio for avibactam >1 (equivalent to 100% fT>CT of 4.0 mg/L) were simultaneously achieved (quasi-optimal if only one of the two was achieved, and suboptimal if neither of the two was achieved). The relationship between ceftazidime-avibactam PK/PD targets and microbiological outcome was assessed. ResultsTen patients with documented CR-GN infections (5 BSIs, 4 VAP, 1 BSI+VAP) were retrieved. The joint PK/PD targets of ceftazidime-avibactam were optimal and quasi-optimal in eight and two cases, respectively. Microbiological failure occurred in two patients (one with VAP, one with BSI+VAP), one of whom developed ceftazidime-avibactam resistance. Both underwent renal replacement therapy, and failed despite attaining optimal joint PK/PD target and receiving fosfomycin co-treatment. ConclusionCI administration may enable optimal joint PK/PD targets of ceftazidime-avibactam to be achieved in most critical renal patients with CR-GN infections, and may help to minimize the risk of microbiological failure.

The risk of inappropriate empiric treatment and its outcomes based on pathogens in non-ventilated (nvHABP), ventilated (vHABP) hospital-acquired and ventilator-associated (VABP) bacterial pneumonia in the US, 2012–2019

BackgroundInappropriate empiric antimicrobial treatment (IET) contributes to worsened outcomes. While IET’s differential impact across types of nosocomial pneumonia (NP: non-ventilated [nvHABP], ventilated [vHABP] hospital-acquired and ventilator-associated [VABP] bacterial pneumonia) is established, its potential interaction with the bacterial etiology is less clear.MethodsWe conducted a multicenter retrospective cohort study in the Premier Healthcare Database using an administrative algorithm to identify NP. We paired respective pathogens with empiric treatments. Antimicrobial coverage was appropriate if a drug administered within 2 days of infection onset covered the recovered organism(s). All other treatment was IET.ResultsAmong 17,819 patients with NP, 26.5% had nvHABP, 25.6% vHABP, and 47.9% VABP. Gram-negative (GN) organisms accounted for > 50% of all infections. GN pathogens were ~ 2 × as likely (7.4% vHABP to 10.7% nvHABP) to engender IET than Gram-positive (GP, 2.9% vHABP to 4.9% nvHABP) pathogens. Although rare (5.6% nvHABP to 8.3% VABP), GN + GP infections had the highest rates of IET (6.7% vHABP to 12.9% nvHABP). Carbapenem-resistant GNs were highly likely to receive IET (33.8% nvHABP to 40.2% VABP). Hospital mortality trended higher in the IET group, reaching statistical significance in GN + GP vHABP (47.8% IET vs. 29.3% non-IET, p = 0.016). 30-day readmission was more common with IET (16.0%) than non-IET (12.6%, p = 0.024) in GN VABP. Generally post-infection onset hospital length of stay and costs were higher with IET than non-IET.ConclusionsIET is ~ 2 × more common in GN than GP infections. Although the magnitude of its impact varies by NP type, IET contributes to worsened clinical and economic outcomes.

Clinical management of cUTI, cIAI, and HABP/VABP attributable to carbapenem-resistant Gram-negative infections in Spain.

IntroductionCarbapenem-resistant Gram-negative (CRGN) infections are a major public health problem in Spain, often implicated in complicated, healthcare-associated infections that require the use of potentially toxic antibacterial agents of last resort. The objective of this study was to assess the clinical management of complicated infections caused by CRGN bacteria in Spanish hospitals.MethodsThe study included: 1) a survey assessing the GN infection and antibacterial susceptibility profile in five participating Spanish hospitals and 2) a non-interventional, retrospective single cohort chart review of 100 patients with complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/ VABP) attributable to CRGN pathogens.ResultsIn the participating hospitals CRGN prevalence was 9.3% amongst complicated infections. In the retrospective cohort, 92% of infections were healthcare-associated, and Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common pathogens. OXA was the most frequently detected carbapenemase type (71.4%). We found that carbapenems were frequently used to treat cUTI, cIAI, HABP/VABP caused by CRGN pathogens. Carbapenem use, particularly in combination with other agents, persisted after confirmation of carbapenem resistance. Clinical cure was 66.0%, mortality during hospitalization 35.0%, mortality at the time of chart review 62.0%, and 6-months-post-discharge readmission 47.7%.ConclusionOur results reflect the high burden and unmet needs associated with the management of complicated infections attributable to CRGN pathogens in Spain and highlight the urgent need for enhanced clinical management of these difficult-to-treat infections.

Complicated carbapenem-resistant infections: a treatment pathway analysis in Italian sites.

Efforts to curb a growing prevalence of carbapenem resistance are prominent worldwide and especially in countries where high levels of carbapenem resistance are reported, such as Italy. Complicated infections, including complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI), and hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), are often caused by carbapenem-resistant Gram-negative (CRGN) bacteria and as such, these infection sites and their causative bacteria are important areas of focus for healthcare practitioners seeking to follow good antimicrobial stewardship practices. The aim of this study was to assess the clinical management and associated clinical and economic outcomes of patients with cUTI, cIAI, and HABP/VABP resulting from CRGN bacteria in Italy. We first conducted a hospital survey focusing on Gram-negative infections and their antibacterial susceptibility profile in four participating Italian hospitals. The second part of the study involved a non-interventional, retrospective single cohort chart review of 100 patients with cUTI, cIAI, or HABP/VABP caused by CRGN bacteria, in which patient characteristics, index hospitalization characteristics, infection characteristics, patient outcomes, treatment pathways, and healthcare resource use were assessed. The hospital survey demonstrated carbapenem resistance in approximately 17% of complicated infections, mostly associated with Acinetobacter baumannii. The non-interventional, retrospective cohort component showed that complicated CRGN infections were hospital- or healthcare-acquired in 99.0% of cases and were most often caused by Klebsiella pneumoniae (66.0%). Despite the carbapenem-resistant nature of the included infections, carbapenems were used in 19.0% of patients as empirical therapy, in 43.0% as late empirical (i.e. immediately before receipt of susceptibility test results), and in 64.0% as targeted therapy (post-susceptibility test result receipt). Colistin was used in 61.0% of patients after susceptibility results were available. High clinical and economic burden was evident, with the average length of hospital stay being greater than 50 days, clinical cure achievement in only 43.0% of patients, and an overall mortality rate of 65.0% by the end of the follow-up period. Our results reflect the considerable burden associated with complicated CRGN infections in Italy and the limitations in current treatment strategies. Our study pinpoints potential areas for improvement. For example, regular and detailed local surveillance and state of the art microbial diagnostic capabilities might aid and hasten clinical decision-making and facilitate improved antimicrobial stewardship when treating complex CRGN infections. New therapeutic options which more appropriately address CRGN infections may assist in improving outcomes which are important to both patients and healthcare providers.

The role of combination therapy in the treatment of severe infections caused by carbapenem resistant gram-negatives: a systematic review of clinical studies

BackgroundEffective treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) remains a challenge for clinicians worldwide. In recent years, the combination of antibiotics has become the preferred treatment strategy for CR-GNB infection. However, robust evidence to support this approach is lacking. This systematic review aimed at critically evaluating all available antibiotic options for CR-GNB sepsis with particular focus on combination.MethodsWe systematically searched published literature from January 1945 until December 2018 for observational comparative and non-comparative studies and randomized trials examining any antibiotic option for CR-GNB. Studies were included if reporting microbiologically-confirmed infection caused by Acinetobacter baumannii, Enterobacteriaceae/Klebsiella spp., or Pseudomonas aeruginosa, reporting at least one of the study outcomes, and definitive antibiotic treatment. Carbapenem-resistance was defined as phenotypically-detected in vitro resistance to at least one of the following carbapenems: doripenem, ertapenem, imipenem, meropenem. Each antibiotic regimen was classified as “defined” when at least the molecular class(es) composing the regimen was detailed. Primary outcomes were 30-day and attributable mortality. Bayesian network meta-analysis (NMA) approach was selected for quantitative synthesis to explore feasibility of pooling data on antibiotic regimens.ResultsA total of 6306 records were retrieved and 134 studies including 11,546 patients were included: 54 studies were on Acinetobacter, 52 on Enterobacteriaceae/Klebsiella, 21 on mixed Gram-negative, and 7 on Pseudomonas. Nine (7%) were RCTs; 19 prospective cohorts (14%), 89 (66%) retrospective, and 17 (13%) case series. Forty-one studies (31%) were multicentric. Qualitative synthesis showed an heterogeneous and scattered reporting of key-clinical and microbiological variables across studies. Ninety-two distinct antibiotic regimens were identified with 47 of them (51%, 5863 patients) not reporting any details on numbers, type, dosage and in vitro activity of the included antibiotic molecules. The NMAs could not be performed for any of the selected outcome given the presence of too many disconnected components.ConclusionThe existing evidence is insufficient to allowing for the formulation of any evidence-based therapeutic recommendation for CR-GNB sepsis. Future studies must provide a standardized definition of antibiotic regimen to drive recommendations for using combination of antibiotics that can be reliably applied to clinical practice.

Determining the burden of infectious diseases caused by carbapenem-resistant gram-negative bacteria in Spain

ObjectiveTo estimate the burden of nosocomial infections induced by carbapenem resistant Gram-negative (CRGN) pathogens in Spain, focusing on both the clinical and economic impact. MethodsThe burden of disease was estimated using data from 2017 according to the availability of data sources. The impact, both clinical and economic, of the most frequent CRGN nosocomial infections (those produced by Klebsiella pneumoniae, Pseudomonasaeruginosa and Acinetobacter baumannii) was analysed. Incidence and mortality of CRGN nosocomial infections were estimated, as well as the direct and indirect costs produced by this health problem. ResultsApproximately 376,346 patients are believed to have suffered a nosocomial infection in Spain in 2017; 3.2% of them due to CRGN bacilli. Infections by carbapenem-resistant P. aeruginosa produced the highest mortality rates (2578 deaths) when compared with A. baumannii (1571) and K. pneumoniae (415). Total economic costs of CRGN nosocomial infections in Spain were estimated to be €472 million in 2017, with 83% of the total cost caused by direct costs. ConclusionCRGN nosocomial infections have a high clinical impact on patients’ lives, high mortality rates, and represent one of the hospitalisation episodes with the most associated costs. Efforts should be focussed to implement preventive policies in order to avoid infections due to CRGN pathogens and the resulting burden, and to reduce direct costs due to morbimortality, specifically in those infections produced by P. aeruginosa.

1271. Efficacy and Safety of Cefiderocol and Best Available Therapy in Patients with Serious Infections Caused by Carbapenem-Resistant Gram-Negative Infections: Results of the Pathogen-Focused Phase 3 CREDIBLE-CR Study

BackgroundThe CREDIBLE-CR study assessed the efficacy and safety of cefiderocol (CFDC), a novel siderophore cephalosporin, in the treatment of serious infections due to carbapenem-resistant (CR) Gram-negative (GN) bacteria.MethodsCREDIBLE-CR was an open-label, prospective, randomized 2:1, Phase 3 study (NCT02714595) in patients with nosocomial pneumonia (NP), bloodstream infections/sepsis (BSI/Sepsis), or complicated urinary tract infections (cUTI) with evidence of CR GN pathogens. Adults received intravenous CFDC 2 g, q8h, 3-h infusion or best available therapy (BAT; up to 3 drugs) for 7–14 days (extendable to 21 days). The primary endpoint at test of cure in the CR microbiological intent-to-treat (CR-MITT) population was clinical cure (NP, BSI/Sepsis) or microbiological eradication (cUTI). Secondary endpoints were clinical and microbiological outcomes, all-cause mortality (ACM) and safety. Only descriptive statistics were pre-specified.ResultsA total of 101 patients received CFDC and 49 received BAT (CR-MITT: CFDC n=80, BAT n=38): 50% had pneumonia, 31.4% BSI/Sepsis, and 18.6% cUTI (Table 1). Most frequent CR pathogens were Acinetobacter baumannii (45.8%), Klebsiella pneumoniae (37.3%), and Pseudomonas aeruginosa (23.7%). CFDC monotherapy was given to 83% of patients, while BAT monotherapy to 29% of patients. Primary outcome in the CFDC and BAT arms was achieved in 50.0% and 52.6% in NP, 43.5% and 42.9% in BSI/Sepsis, and 52.9% and 20.0% in cUTI patients (Figure). CFDC was highly efficacious vs CREs and NDM-producing pathogens. Day 28 ACM was 24.8% (25/101) with CFDC and 18.4% (9/49) with BAT. Rescue therapy was given more frequently in the BAT than CFDC arm. Mortality results by pathogen showed an imbalance in Acinetobacter spp. infections (Table 2) with a higher rate in the CFDC arm than BAT arm. ICU and shock at randomization were more frequent in the CFDC arm than in the BAT arm in Acinetobacter spp. infections (Table 2). No safety concerns related to CFDC emerged.Table 1. Baseline demographics and characteristics (CR-MITT population) Figure. CREDIBLE-CR study primary efficacy endpoints and secondary outcomes at test-of-cure visit in CR-MITT population. Table 2. All-cause mortality by baseline pathogen inpatients with or without Acinetobacter spp. infection (safety population) ConclusionEfficacy of CFDC was demonstrated in this descriptive pathogen-focused study, including CREs, metallo-NDM producers and CR non-fermenters. Baseline imbalances of ICU and shock in the subset of infections with Acinetobacter spp. may have contributed to the mortality difference between CFDC and BAT arms.DisclosuresMatteo Bassetti, MD, Shionogi Inc. (Advisor or Review Panel member) Roger Echols, MD, Shionogi Inc. (Consultant) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Kiichiro Toyoizumi, PhD, Shionogi & Co., Ltd. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee)

1266. Characterization of Shifts in Minimum Inhibitory Concentrations During Treatment with Cefiderocol or Comparators in the Phase 3 CREDIBLE-CR and APEKS-NP Studies

BackgroundCefiderocol (CFDC) is a novel siderophore cephalosporin developed to treat serious carbapenem-resistant (CR) Gram-negative (GN) infections.MethodsIn CREDIBLE-CR (NCT02714595), adults with serious infections caused by CR GN pathogens received CFDC 2 g, q8h, 3-h infusion, or best available therapy (BAT). In APEKS-NP (NCT03032380), adults with nosocomial pneumonia received CFDC or high-dose, extended-infusion meropenem (each 2 g, q8h, 3-h infusion). All treatments were given for 7‒14 days (extendable to 21 days). Biospecimens were collected before the first dose of study drug and at subsequent visits for assessments, and minimum inhibitory concentrations (MIC) to various antibiotics, including CFDC and carbapenems, were determined. Isolates with an increased MIC were evaluated by RT-PCR or whole genome sequencing (WGS) for CFDC resistance-related genes or mutations. Results for genetically related isolates with an elevated MIC during therapy are shown.ResultsOn-therapy ≥4-fold CFDC MIC increase was found in 12 out of 106 (CREDIBLE-CR; Table 1) and 7 out of 159 (APEKS-NP; Table 2) isolates, respectively. For most isolates, CFDC MIC increased by 4–8-fold but remained ≤4 µg/mL. Specific mutations which could explain CFDC MIC increases were found in only 3 isolates. Mutations in iron-transport related genes were not identified. Mutation in CFDC target gene PBP-3 was identified in 1 A. baumannii isolate. Class-C enzyme mutation was observed in 2 isolates (CREDIBLE-CR: PDC-30 in P. aeruginosa; APEKS-NP: ACT-17 in E. cloacae), although the contribution to CFDC MIC increase has not been confirmed. In the BAT arm in CREDIBLE-CR, 6 out of 46 isolates had ≥4-fold MIC increase; all post-treatment isolates were resistant to BAT agents (Table 1), although WGS was not conducted for these isolates. In the meropenem arm in APEKS-NP, 5 out of 164 isolates had ≥4-fold MIC increase (Table 2).Table 1. MIC changes in CREDIBLE-CR Table 2. MIC changes in APEKS-NP ConclusionAmong isolates with ≥4-fold MIC increase during CFDC treatment, actual CFDC MIC values remained relatively low for most isolates. Frequency of MIC increase in BAT or meropenem arms was similar to that of CFDC, but the magnitude was greater. Acquisition of contributory mechanism has not been identified except for the mutation in PBP 3 and some β-lactamases.DisclosuresMiki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee)

Burden of carbapenem non-susceptible infections in high-risk patients: systematic literature review and meta-analysis

BackgroundOwing to their resistance to an important class of antibiotics, the prevention and treatment of carbapenem-resistant (CR)/non-susceptible Gram-negative (GN) infections has become an important public health objective. We conducted a systematic review and meta-analysis of published literature to evaluate the burden of CR GN infections, focusing on high-risk patients such as transplant recipients, or patients with cancer, renal impairment, or sepsis.MethodsMEDLINE®, Cochrane Central, and Embase® were searched between 2010 and March 2019. s and full-text articles were screened in duplicate. Random effects meta-analysis was conducted when reported outcomes were sufficiently similar.ResultsTwenty-six publications were eligible. Meta-analyses found increased mortality associated with CR infections among high-risk patients in both unadjusted analysis (8 studies; summary unadjusted odds ratio [OR]: 5.85; 95% confidence interval [CI]: 3.69, 9.26; I2 = 19.8%) and adjusted analysis (5 studies; summary hazard ratio [HR]: 4.67; 95% CI: 2.18, 9.99; I2 = 77.7%), compared to patients with carbapenem-susceptible (CS) infections or no infection. Increased mortality was also seen in subgroup analyses by length of follow-up (either short-term or long-term) or causative pathogen. A limited number of studies found that CR GN infections increased the risk for mechanical ventilation, adverse events such as graft failure or acute rejection in solid organ transplant recipients, increased renal failure or nephrotoxicity, and an increase in readmissions and costs, though the findings reported in the literature were not consistent.ConclusionThis systematic literature review and meta-analysis indicates that CR GN infections in high-risk patients are associated with increased mortality, emphasizing the need for antimicrobial stewardship and infection control in hospitals which treat high-risk patients and for the development of effective antimicrobials with favorable efficacy and safety profiles for the treatment of CR GN infections.

Insights into the Clinical Management of Carbapenem-Resistant Gram-Negative Infections: An Italian Retrospective Clinical Chart Review

There is a lack of consensus regarding management of infections with carbapenem- resistant Gram-negative (CR-GN) pathogens. This study comprised a medical chart review to assess patient management in a high CR prevalence setting. Data was collated retrospectively from medical records of patients hospitalized between November 1st, 2015 and October 31st, 2016. Of 29 patients, 66% had respiratory tract infections. Median duration of hospitalization was 28 days and ~50% of patients were admitted to the intensive care unit, with 77% remaining for >2 weeks. Median time to obtain respiratory culture results was 5 days. Isolation of patients with diagnosed CR-GN infection took ≥5 days in >50% of patients. A majority (76%) of patients received ≥1 antibiotic before providing a specimen for culture; a total of 17 antibiotic treatments were used. Overall, 72% of patients, and 68% of those with respiratory infections, were discharged alive; 38% were discharged without further antibiotics. The difficulties in achieving effective management in patients with CR-GN infections are largely due to complex co-morbidities, a history of prior antibiotic treatment, and multiple referrals across health care facilities.

Determining the burden of infectious diseases caused by carbapenem-resistant gram-negative bacteria in Spain

ObjectiveTo estimate the burden of nosocomial infections induced by carbapenem resistant Gram-negative (CRGN) pathogens in Spain, focusing on both the clinical and economic impact. MethodsThe burden of disease was estimated using data from 2017 according to the availability of data sources. The impact, both clinical and economic, of the most frequent CRGN nosocomial infections (those produced by Klebsiella pneumoniae, Pseudomonasaeruginosa and Acinetobacter baumannii) was analysed. Incidence and mortality of CRGN nosocomial infections were estimated, as well as the direct and indirect costs produced by this health problem. ResultsApproximately 376,346 patients are believed to have suffered a nosocomial infection in Spain in 2017; 3.2% of them due to CRGN bacilli. Infections by carbapenem-resistant P. aeruginosa produced the highest mortality rates (2578 deaths) when compared with A. baumannii (1571) and K. pneumoniae (415). Total economic costs of CRGN nosocomial infections in Spain were estimated to be €472 million in 2017, with 83% of the total cost caused by direct costs. ConclusionCRGN nosocomial infections have a high clinical impact on patients’ lives, high mortality rates, and represent one of the hospitalisation episodes with the most associated costs. Efforts should be focussed to implement preventive policies in order to avoid infections due to CRGN pathogens and the resulting burden, and to reduce direct costs due to morbimortality, specifically in those infections produced by P. aeruginosa.

Colistin plus meropenem for carbapenem-resistant Gram-negative infections: in vitro synergism is not associated with better clinical outcomes

ObjectivesIn vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem. MethodsThis was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin–meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin–meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure. ResultsThe sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31–1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22–2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26–1.04) or 14-day mortality (aOR1.09, 95% CI 0.60–1.96). DiscussionIn vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit.

2665. Intestinal Microbiome of Patients Submitted to Hematopoietic Stem Cell Transplantation Using Lactobacillus plantarum to Decolonized Multidrug-Resistant Bacteria

BackgroundPatients colonized by multidrug-resistant bacteria (MDR) have high risk for infection after hematopoietic stem cell transplantation (HSCT). Probiotic is a strategy that can be used to decolonize patients. Our aim was to describe the impact of use of Lactobacillus plantarum (LP) on decolonization, MDR infections and intestinal microbiome (IM) of autologous HSCT patients colonized by vancomycin-resistant Enterococcus (VRE) and carbapenem-resistant Gram-negative (CRGN).MethodsA prospective study was conducted at Hospital das Clinicas of University of Sao Paulo Brazil from 2017 to 2018. Candidates for auto-HSCT colonized by MDR received LP in capsules, 5 × 109 CFU twice daily until neutropenia (NP). Rectal swabs were performed and cultured using selective media as well as PCR for carbapenemases, vanA and vanB. Stool samples for IM analysis were collected weekly as baseline (before LB use) until the NP. The V4 region of 16S rDNA gene were sequenced by Ion Torrent PGM and analyzed using alpha and β diversities by Qiime. Demographic and clinical data including previous antibiotics use were evaluated; CDC criteria was applied for colonization and infection.ResultsAll of seven patients were colonized by VRE and CRGN (Table 1). Only one patient remained colonized by CRGN after 61 days of LP. Four patients developed seven bloodstream infections (BSI) during the NP, two of them by CRGN. There was no infection caused by VRE neither by LP. One patient, with low adherence to LP use (66%), died due to MDR K. pneumoniae BSI. We observed a decrease of Clostridia, Verrucomicrobiae, Blautia and an increase of Enterobacteriaceae. Baseline samples from patients who used TMP/SMX had higher concentrations of Bacteroidetes when compared with those who had not use it. The Shannon index in controls ranged 1.98–5.55 and during NP 1.15–5.99. The β diversity analysis showed no clear patterns between patients.ConclusionWe observed a heterogeneity among IM of auto-HSCT patients prior and after LP. It was not possible to establish an IM pattern, probably, because of small number of patients. Although, clinical infections by CRGN occurred despite of LP use, no cases of colonization and infection by VRE were identified. Thus, it seems that LP is a good and safe strategy to decolonized HSCT. Disclosures All authors: No reported disclosures.

Impact of bloodstream infections caused by carbapenem-resistant Gram-negative pathogens on ICU costs, mortality and length of stay

SummaryBackgroundThe aim of this study was to estimate the impact of bloodstream infections (BSIs) caused by carbapenem-resistant Gram-negative (CRGN) pathogens on hospital costs, mortality and length of stay (LOS).MethodsAll patients hospitalized for ≥3 days in the Intensive Care Unit (ICU) of a tertiary-care general hospital from 1/1/2015 to 31/12/2017 were included in the study. A retrospective case-control study was performed in order to examine the difference in medical, pharmaceutical and operating costs, LOS and in-hospital mortality between patients with BSI caused by CRGN/without BSI (cases/controls, respectively). The statistical analysis was performed using the SPSS software (v23.0).ResultsA total of 419 patients (67.5% males, median age 60.0 years) were included in the analysis (142 cases/277 controls); 10 patients with non-CRGN BSIs were excluded. Overall mortality was 33.7% (49.3/25.6% in cases/controls). The median LOS and total cost were 30.0 vs. 12.0 days and 20 359.1 vs. 8,509.3 €, respectively, between patients with/without CRGN BSIs. After adjusting for baseline demographics, underlying disease severity and patients' specialties, CRGN BSIs remained a significant factor in mortality (odds ratio 2.9; 95% confidence interval 1.8–4.8; p <0.001). Additionally, CRGN BSIs seem to result in significantly prolonged LOS and extra cost per infected patient (p <0.001).ConclusionsICU patients with CRGN BSI are at increased risk for mortality and prolonged hospitalization and incur higher costs, imposing a heavy burden on healthcare system. Infection control strategies, considering also the cost-efficacy of interventions, are crucial in order to control the expansion of CRGN infections.