Carbapenem-resistant Organisms Research Articles

Carbapenems versus Cephalosporin or Piperacillin-Tazobactam as Perioperative Antibiotic Prophylaxis in Liver Transplant Recipients with Model for End-Stage Liver Disease Scores of ≥30: A Retrospective Study in a Chinese Population.

ObjectivePerioperative prophylaxis, commonly with a third-generation cephalosporin plus ampicillin or piperacillin-tazobactam, is usually employed to prevent infections in liver transplantation (LT) recipients. Patients with a high Model for End-Stage Liver Disease (MELD) score have an increased infection risk after LT. However, whether carbapenems could be used as surgical prophylaxis in these high-risk patients remains unclear. Therefore, this study aimed at comparing the effectiveness of carbapenems with that of cephalosporin or piperacillin-tazobactam for surgical prophylaxis in high-risk LT recipients with a MELD score ≥30.Design or MethodsThis retrospective study included adult patients with a MELD score ≥30 who underwent LT between May 2018 and September 2020. We comparatively analyzed the infection rate and outcome between patients using cefoperazone-sulbactam or piperacillin-tazobactam and those using carbapenems as surgical prophylaxis.ResultsThis study included 105 LT recipients. Seventy-eight and 27 patients used non-carbapenem and carbapenem antibiotics, respectively, as surgical prophylaxis. The corresponding infection incidence rates within 30 days were 38.5% and 66.7% (p = 0.011). Multivariate analysis revealed that reoperation and the Child–Pugh score were independent risk factors for infections within 30 days after LT. The following four risk factors were associated with the 180-day post-LT survival: MELD score, vascular complication, intra-abdominal bleeding, and infection with carbapenem-resistant organisms (CROs). There was no significant difference in CRO infection incidence between the carbapenem and non-carbapenem groups (18.5% vs 11.5%; p = 0.345).ConclusionCarbapenem use as surgical prophylaxis was not associated with infection incidence within 30 days after LT, 180-day post-LT survival or CRO infection. Therefore, carbapenems are not superior to cephalosporin or piperacillin-tazobactam for perioperative antibiotic prophylaxis in LT recipients with a MELD score ≥30.

Comprehensive Surveillance and Sampling Reveal Carbapenem-Resistant Organism Spreading in Tertiary Hospitals in China.

PurposeCarbapenem-resistant organisms (CROs) have posed a great threat to antibiotic use and induce multi-drug resistance. Contamination of the hospital environment and infection of healthcare workers (HCWs) are reported as sources of nosocomial infections. Here, we performed a comprehensive environment sampling and timely epidemiological investigation during outbreaks to investigate the role of the environment and HCWs in CRO transmission.Patients and MethodsWe enrolled carbapenem-resistant organism outbreaks in ICU-1 of Huashan Hospital from January 2019 to March 2019, and ICU-2 located at west branch of Huashan Hospital from October 2019 to November 2019. Carbapenem-resistant Klebsiella pneumoniae (CRKP) and carbapenem-resistant Acinetobacter baumannii (CRAB) isolates were collected from the patients. We performed a real-time comprehensive environmental and HCW sampling in the two ICUs. Isolated strains from patients and the positive colonies from the screening were sent for whole-genome sequencing. Finally, phylogenetic trees were constructed.ResultsCRAB and CRKP outbreaks simultaneously occurred in ICU-1; the outbreak involved 13 patients. Meanwhile, the CRKP outbreak in ICU-2 included 11 patients. Twelve out of 146 environment and HCWs samples in ICU-1 were carbapenem-resistant bacteria, including six CRKP and six CRAB strains. For ICU-2, hospital surfaces and HCWs were negative for CRKP. Phylogenetic analyses showed that CRKP strains in ICU-1 were classified into two clades: Clade 1 and Clade 2, sharing a high similarity of isolates from the environment and HCWs. The same phenomenon was observed in CRAB.ConclusionA timely comprehensive sampling combined with genome-based investigation may aid in tracking the transmission route of and controlling the infections. The environment and HCWs could be contaminated during CRO transmission, which calls for strengthened prevention and control measures.

Comparative Analysis of Bacterial Microflora Isolated from Adult Pneumonia Inpatients and Hospital Objects in the Amur Region

Background: The COVID-19 pandemic has exacerbated the problem of healthcare-associated infections and worsened the situation with the hospital spread of antibiotic resistant strains potentially inducing nosocomial infections. Objective: To compare bacterial microflora isolated from adult pneumonia inpatients and hospital objects and to assess the risk of hospital-acquired infections in the Amur Region. Materials and methods: The study was conducted in a multidisciplinary and a “COVID” hospital hereinafter referred to as Hospitals 1 and 2, respectively. Parallel bacteria culture testing of 519 sputum samples from 284 inpatients and 486 wipe samples collected weekly during 12 weeks in both hospitals was carried out using a classical method. AutoSCAN-4 and Vitek® 2 Compact 30 analyzers were applied to identify pathogens and determine their antimicrobial susceptibility. Results: Along with the detection of pathogenic bacteria in 33.8 % of hospitalized patients with pneumonia, we found pathogens in 23.3 % and 12.4 % of wipe samples from Hospitals 1 and 2, respectively, and established that the proportion of Gram-negative bacteria in them was 44.9 % and 15.4 % while the share of multidrug-resistant strains was 32.7 % and 3.8 %. The significant differences observed can be attributed to a more stringent disinfection regime in Hospital 2. The structure of multidrug-resistant Gram-negative bacteria was noted for a high proportion of carbapenem-resistant organisms isolated from both sputum (20.0 %) and wipe (38.9 %) samples. Conclusion: Our monitoring results helped define the composition and ratio of bacterial pathogens isolated from pneumonia cases and hospital objects. A wide range of pathogens, including those resistant to antibiotics, often detected in wipe samples and their accumulation over time indicate the potential hazard of the hospital environment posing an increased risk of hospital-acquired infections.

Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae.

Co-administration of antibiotics with synergistic effects is one method to combat carbapenem-resistant organisms. Although the synergistic effects of tigecycline combined with aminoglycosides against carbapenem-resistant Klebsiella pneumoniae (CRKP) have been demonstrated in vitro and in animal models, the underlying mechanism remains elusive. Here we used proteomics analysis to assess the short-term bacterial responses to tigecycline and aminoglycosides alone or in combination. Emergence of tigecycline resistance during treatment and the susceptibility of tigecycline-resistant strains to aminoglycosides was further evaluated. The proteomic responses to tigecycline and aminoglycosides were divergent in monotherapy, with proteomic alterations to combination therapy dominated by tigecycline. Adaptive responses to tigecycline were associated with the upregulation of oxidative phosphorylation and translation-related proteins. These responses might confer CRKP hypersensitivity towards aminoglycosides by increasing the drug uptake and binding targets. Meanwhile, tigecycline might perturb adaptive responses to aminoglycosides through inhibition of heat shock response. Tigecycline-resistant strains could be isolated within 24 h exposure even in strains without heteroresistance, and the sensitivity to aminoglycosides significantly increased in resistant strains. Overall, these findings demonstrated that adaption to tigecycline in CRKP was a double-edged sword associated with the synergistic killing in tigecycline–aminoglycoside combination. Evolutionary hypersensitivity can provide novel insight into the mechanisms of antibiotic synergistic effects.

Population Pharmacokinetics of Colistin Sulfate in Critically Ill Patients: Exposure and Clinical Efficacy.

Background: Presently, colistin is commercially available in two different forms, namely, colistin sulfate and its sulphomethylated derivative, colistimethate sodium (CMS). However, in the currently reported studies, most of the clinical studies on colistin for parenteral use are referred to as CMS. Data on the pharmacokinetics (PK), clinical efficacy, and side effects of colistin sulfate in clinical use have not been reported. Methods: This retrospective study was performed on carbapenem-resistant organism (CRO)-infected patients treated with colistin sulfate for more than 72 h. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological eradication, and nephrotoxicity were assessed. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients with normal or decreased renal function. Results: A total of 42 patients were enrolled, of which 25 (59.52%) patients were considered clinical treatment success and 29 (69.06%) patients had successful bacteria elimination at the end of treatment. Remarkably, no patient developed colistin sulfate-related nephrotoxicity. A total of 112 colistin concentrations with a range of 0.28–6.20 mg/L were included for PK modeling. The PK characteristic of colistin was well illustrated by a one-compartment model with linear elimination, and creatinine clearance (CrCL) was identified as a covariate on the clearance of colistin sulfate that significantly explained inter-individual variability. Monte Carlo simulations showed that the recommended dose regimen of colistin sulfate, according to the label sheet, of a daily dose of 1–1.5 million IU/day, given in 2–3 doses, could attain PTA > 90% for MICs ≤ 0.5 μg/mL, and that a daily dose of 1 million IU/day could pose a risk of subtherapeutic exposure for MIC ≥1 μg/ml in renal healthy patients. Conclusion: Renal function significantly affects the clearance of colistin sulfate. A dose of 750,000 U every 12 h was recommended for pathogens with MIC ≤1 μg/ml. The dosage recommended by the label inserts had a risk of subtherapeutic exposure for pathogens with MIC ≥2 μg/ml. Despite higher exposure to colistin in patients with acute renal insufficiency, dose reduction was not recommended.

Pharmacokinetics and Pharmacodynamics of Colistin Methanesulfonate in Healthy Chinese Subjects after Multi-Dose Regimen.

Colistin methanesulfonate (CMS) is an important treatment option for infections caused by carbapenem-resistant Gram-negative organisms (CROs). This study evaluated the pharmacokinetic/pharmacodynamic (PK/PD) profiles and safety of CMS in Chinese subjects following a recommended dosage. A total of 12 healthy Chinese subjects received CMS injections at 2.5 mg/kg once every 12 h for 7 consecutive days. The PK/PD profiles of the active form of CMS, colistin, against CROs were analyzed with the Monte Carlo simulation method. No serious adverse events were observed. The average steady-state plasma concentrations of CMS and colistin were 4.41 ± 0.75 μg/mL and 1.27 ± 0.27 μg/mL, and the steady-state exposures (AUC0–12,ss) were 52.93 ± 9.05 h·μg/mL and 15.28 ± 3.29 h·μg/mL, respectively. Colistin, at its minimum inhibitory concentration (MIC) of 0.5 μg/mL, has >90% probability to reduce CROs by ≥1 log. The PK/PD breakpoints for the ≥1 log kill were ≥MIC90 for carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa, but were ≤MIC50 for carbapenem-resistant Acinetobacter baumannii. The recommended dose regimen of CMS for 7 consecutive days was safe in Chinese subjects. The systemic exposure of colistin showed a high probability of being sufficient for most CROs, but was not sufficient for some carbapenem-resistant A. baumannii.

Polymyxin B/Tigecycline Combination vs. Polymyxin B or Tigecycline Alone for the Treatment of Hospital-Acquired Pneumonia Caused by Carbapenem-Resistant Enterobacteriaceae or Carbapenem-Resistant Acinetobacter baumannii.

IntroductionIt is not clear whether polymyxin B/tigecycline (PMB/TGC) combination is better than PMB or TGC alone in the treatment of hospital-acquired pneumonia (HAP) caused by carbapenem-resistant organisms (CROs).MethodsWe conducted a multicenter, retrospective cohort study in patients with HAP caused by CROs. The primary outcome was 28-day mortality, and the secondary outcomes included clinical success and the incidence of acute kidney injury (AKI). Multivariate Cox regression analysis was performed to examine the relationship between antimicrobial treatments and 28-day mortality by adjusting other potential confounding factors.ResultsA total of 364 eligible patients were included in the final analysis, i.e., 99 in the PMB group, 173 in the TGC group, and 92 in the PMB/TGC combination group. The 28-day mortality rate was 28.3% (28/99) in the PMB group, 39.3% (68/173) in the TGC group, and 48.9% (45/92) in the PMB/TGC combination group (p = 0.014). The multivariate Cox regression model showed that there was a statistically significant lower risk of 28-day mortality among participants in the PMB group when compared with the PMB/TGC combination group [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31–0.81, p = 0.004] and that participants in the TGC group had a lower risk of 28-day mortality than in the PMB/TGC combination group but without statistical significance. The incidence of AKI in the PMB group (52.5%) and the PMB/TGC combination group (53.3%) was significantly higher than that in the TGC group (33.5%, p = 0.001).ConclusionThe appropriate PMB/TGC combination was not superior to appropriate PMB therapy in the treatment of HAP caused by carbapenem-resistant Enterobacteriaceae/carbapenem-resistant Acinetobacter baumannii (CRE/CRAB) in terms of 28-day mortality.

A waterfall of susceptibility results: impact of microbiology testing cascade for MDROs

Cascade reporting is an antimicrobial stewardship strategy which selectively reports broad-spectrum antibiotic susceptibility when narrower-spectrum agents are resistant. Three regional laboratories, which provide microbiology services for HCA Healthcare hospitals in Florida, implemented a standardized antibiotic testing cascade for multi-drug resistant organisms. This study evaluated the impact of the testing cascade on time to susceptibility results for carbapenem-resistant Gram-negative organisms. Appropriateness of manual susceptibility test selection was also assessed. Compliance with the testing cascade was 56%. Appropriateness of manual tests in the pre- and post-intervention groups was 87% (257/297) and 96% (310/323), respectively (P < 0.0001). Median time to first manual test result was 23.1 hours (IQR: 19.8−25.2 hours) in the pre-intervention group and 23.9 hours (IQR: 20.2−27.0 hours) in the post-intervention group (P = 0.11). Implementation of a testing cascade did not result in faster manual susceptibility results, however there was a significant increase in testing appropriateness.

Population pharmacokinetics of polymyxin B and dosage strategy in critically ill patients with/without continuous renal replacement therapy

Polymyxin B is served as a last-line agent for Carbapenem-resistant organisms (CRO) infections. This study aimed to establish a population pharmacokinetic (PK) model in patients with/without continuous renal replacement therapy (CRRT), to investigate the relationship between clinical covariates and polymyxin B PK parameters, and to optimize polymyxin B dosing regimens. Blood samples were obtained for each patient at steady state. The plasma concentrations of polymyxin B were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Population PK models were developed using Pirana program and Monte Carlo simulations were conducted. A total of 63 patients accounting for 189 blood samples were included and divided into modeling (n = 49) and validation (n = 14) groups. A two-compartment model described the data well. CRRT, creatinine clearance (CLCR) and Sequential Organ Failure Assessment (SOFA) score were identified as significant covariates of polymyxin B clearance. Monte Carlo simulations indicated that a maintain dose of 75–100 mg q12h was required to meet the target drug exposure in patients receiving CRRT with SOFA ≤ 11 (minimum inhibitory concentration ≤ 1 mg·L−1). For patients without CRRT, dosage strategy should be adjusted on the basis of different renal functions and SOFA scores. This is the first population PK study that demonstrated CRRT, CLCR and SOFA score had significant effects on polymyxin B clearance in critically ill patients with/without CRRT. More PK data are urgently needed to clarify polymyxin B PK characteristics in patients with/without CRRT.

Drug Resistance and Risk Factors for Acquisition of Gram-Negative Bacteria and Carbapenem-Resistant Organisms Among Liver Transplant Recipients.

IntroductionInfections caused by Gram-negative bacteria, in particular carbapenem-resistant organisms (CRO), pose a great threat to liver transplant (LT) recipients. Understanding the risk factors for Gram-negative and CRO infections and the drug resistance of corresponding bacteria will help guide the prevention and treatment of these infections.MethodsData on the composition, distribution and drug resistance of Gram-negative bacteria and CRO among LT recipients were collected. The risk factors for Gram-negative and CRO infections were identified via univariate and multivariate analysis.ResultsA total of 45 episodes of Gram-negative infection, including 20 episodes of CRO infection, occurred in 19.9% (27/136) of LT recipients. Klebsiella pneumoniae was the dominant pathogenic bacteria (14/45; 31.1%). The most common site of infection was the abdominal cavity/bile duct (11/27; 40.7%). Eleven (8.1%) patients died within 2 months after LT, and two deaths were related to Gram-negative infection. Gram-negative bacteria were relatively sensitive to tigecycline and polymyxin B, with resistance of 26.7 and 11.1%, respectively. CRO had lower resistance to ceftazidime/avibactam (45.5%) and polymyxin B (10%). A univariate analysis showed that male sex, infection within 2 months prior to LT, duration of surgery ≥ 400 min, reoperation, indwelling urethral catheter use ≥ 3 days and elevated alanine aminotransferase on day 1 post-LT were associated with Gram-negative infection. Multivariate logistic regression analysis revealed that infection within 2 months prior to LT [odds ratio (OR) = 4.426, 95%CI: 1.634–11.99, P = 0.003], duration of surgery ≥ 400 min [OR = 3.047, 95%CI: 1.194–7.773, P = 0.02] and indwelling urethral catheter use ≥ 3 days [OR = 5.728, 95%CI: 1.226–26.763, P = 0.026] were independent risk factors for Gram-negative infection after LT, and that only carbapenem use ≥ 3 days within 15 days prior to infection [OR = 14, 95%CI: 1.862–105.268, P = 0.01] was related to the occurrence of CRO infections.ConclusionThe incidence of Gram-negative and CRO infections was high in the early post-LT period. The most common infection site was the abdominal cavity/bile duct, and the dominant pathogen was K. pneumoniae. Patients with infections within 2 months prior to LT, prolonged surgery time or delayed urethral catheter removal were prone to Gram-negative infection. Carbapenem exposure was correlated with CRO infections.

Epidemiological, Clinical and Microbiological Characteristics of Patients with Bloodstream Infections Due to Carbapenem-Resistant K. Pneumoniae in Southern Italy: A Multicentre Study.

Background: In the present study, our aim was to evaluate the clinical and microbiological characteristics of a cohort of patients with bloodstream infections (BSI) due to Carbapenem-Resistant Enterobacteriaceae (CRE) and investigate the independent predictors of mortality. Methods: All episodes of carbapenem-resistant E. coli (CREc) or K. pneumoniae (CRKp) BSI that were subject to a mandatory notification from January to December 2020 in all acute care hospitals and long-term care facilities of the Campania region in southern Italy were enrolled. All carbapenem-resistant strains were assessed through molecular tests for the presence of five carbapenemase gene families, i.e., K. pneumoniae Carbapenemase (KPC), oxacillinase-48 (OXA-48), New Delhi Metallo-β-lactamase (NDM), Verona integron encoded metallo-β-lactamase (VIM) and Imipenemase (IMP). Results: During the study period, a total of 154 consecutive non-repeated CRE BSI, all due to CRKp, were reported. The most frequently identified genes were KPC in 108 cases (70.1%), followed by metallo-betalactamases (MBL) (16.2%), and OXA-48 (2.6%); in 17 isolates (11%) no carbapenemase was detected. The overall mortality at 90 days was 41.9%. Using a log-rank test, patients without risk factors for CRE infections showed a significantly lower cumulative mortality (p = 0.001). After multivariate logistic regression analysis, the presence of at least one risk factor was the only predictor of mortality (OR: 1.7, 95% CI 1.2–6.1, p = 0.015). Conclusions. The study reported a non-negligible prevalence of MBL-producing organisms among CRKp isolated from blood cultures in our region. This data highlights the importance of molecular characterization of all clinical isolates of carbapenem-resistant organisms.

Plasma concentrations of Colistin sulfate in a patient with septic shock on extracorporeal membrane oxygenation and continuous renal replacement therapy: a case report

BackgroundPolymyxins antibiotics have become the first-line clinical drugs in the treatment of refractory gram-negative bacterial infections. Currently, there is a lack of clinical studies on the effect of extracorporeal membrane oxygenation (ECMO) combined with continuous renal replacement therapy (CRRT) on polymyxin concentrations. The purpose of this report was to investigate the changes in the plasma concentrations of Colistin sulfate during ECMO and CRRT and to provide drug administration programs for critically ill patients receiving ECMO and CRRT.Case DescriptionIn this case report, a patient with septic shock caused by severe acute pancreatitis, with abdominal pain and dyspnea as the main manifestations, was treated with ECMO combined with CRRT for life support and multiple anti-infective drugs. However, the symptoms of infection had not got improved, the inflammatory indicators remain high and the body temperature fluctuates repeatedly 36.7–38.5 ℃, was considered as carbapenem-resistant organisms (CROs) infection, and was empirically given Colistin sulfate for anti-infection treatment. Finally, the patient’s condition improved and ECMO and CRRT were gradually withdrawn. At the same time, the plasma concentrations of Colistin sulfate before and after ECMO combined with CRRT, was monitored to determine the changes in the plasma concentrations of Colistin sulfate during ECMO and CRRT. Trough and peak concentrations on the 4th day of venovenous ECMO (VV-ECMO) combined with CRRT were 0.36 and 0.98 mg/L, respectively. After withdrawal of ECMO and CRRT, the concentrations were, respectively, 0.27 and 0.34 mg/L for trough concentrations, and 0.82 and 0.98 mg/L for peak concentrations. The data showed that there were no significant differences in the trough and peak concentrations of Colistin sulfate before and after ECMO and CRRT. No adverse effects occurred during follow-up.ConclusionsThere were no significant differences in the trough and peak concentrations of Colistin sulfate before and after ECMO and CRRT. Therefore, no dose modification is required for Colistin sulfate in patients receiving ECMO with CRRT.

A Variant Carbapenem Inactivation Method (CIM) for Acinetobacter baumannii Group with Shortened Time-to-Result: rCIM-A.

Carbapenem-resistant Acinetobacter baumannii group organisms (CRAB) are challenging because the choice between targeted, new antibiotic drug options and hygiene measures should be guided by a timely identification of resistance mechanisms. In CRAB, acquired class-D carbapenemases (CHDLs) are active against meropenem and imipenem. If PCR methods are not the first choice, phenotypic methods have to be implemented. While promising, the carbapenemase inactivation method (CIM) using meropenem-hydrolysis is, however, hampered by poor performance or overly long time-to-result. We developed a rapid CIM (rCIM-A) with good performance using ertapenem, imipenem, and meropenem disks, 2-h permeabilization and incubation with the test strain in trypticase soy broth, and a read-out of residual carbapenem activity after 6 h, and optionally after 16–18 h. Using clinical isolates and type-strains of Acinetobacter (n = 67) not harboring carbapenemases (n = 28) or harboring acquired carbapenemases (n = 39), the sensitivity of detection was 97.4% with the imipenem disk after 6 h at a specificity of 92.9%. If the inhibition zone around the ertapenem disk at 6 h was 6 or ≤26 mm at 16–18 h, or ≤25.5 mm for meropenem, the specificity was 100%. Because of the high negative predictive value, the rCIM-A seems particularly appropriate in areas of lower CRAB-frequency.

Analysis of Ceftazidime/Avibactam Use for Treating Carbapenem-Resistant Infections in Critically Ill Patients With Thermal or Inhalation Injuries.

Rising antimicrobial resistance is a pressing public health concern. An increase in carbapenem-resistant organisms has led to increased use of novel antibiotics, such as ceftazidime/avibactam (CZ/AV). However, recent studies have shown increasing treatment failures and resistance rates associated with ceftazidime/avibactam use. The efficacy of CZ/AV has not been studied in patients with thermal or inhalation injuries, where pharmacokinetic derangements are common and patients are often subject to longer lengths of stay and several antimicrobial courses that may lead to higher resistance rates. The objective of this study was to evaluate the outcomes of patients with thermal and inhalation injuries including clinical success, the frequency of adverse effects, and emergence of resistance. In the 17 courses of CZ/AV evaluated, clinical success occurred in 71% (12/17) of courses. Enterobacter cloacae was the most commonly treated pathogen. Resistance developed in 18% (3/17) of courses, but follow-up sensitivities were not evaluable for every case. Although lower than desired, clinical success rates in this sample were similar to other reported populations treated with CZ/AV. However, the emergence of resistance occurred more frequently and was likely underreported in this sample. Although limited by its small sample size, this study emphasizes the concern of growing antimicrobial resistance among even novel antibiotics. Resistance can develop during the initial course, stressing the importance of infection prevention and antimicrobial stewardship. Furthermore, attention and resources should be given to proper pharmacokinetic analysis of medications given in severely ill, hypermetabolic populations.

Risk Factors for Mortality Among Critical Acute Pancreatitis Patients with Carbapenem-Resistant Organism Infections and Drug Resistance of Causative Pathogens.

IntroductionCarbapenem-resistant organisms (CRO) have emerged as a major global public health threat, but their role in critical acute pancreatitis (CAP) is still not defined. Our study aims to investigate risk factors associated with mortality and drug resistance among CAP patients with CRO infection.MethodsThe clinical characteristics of CAP patients with CRO infection and drug resistance of causative pathogens from January 1, 2016, to October 1, 2021, were reviewed retrospectively. Independent risk factors for mortality were determined via univariate and multivariate analyses.ResultEighty-two CAP patients suffered from CRO infection, with mortality of 60.0%. The independent risk factors for mortality were procalcitonin > 5 ng/L (hazard ratio = 2.300, 95% confidence interval = 1.180–4.484, P = 0.014) and lactic acid > 2 mmol/L (hazard ratio = 2.101, 95% confidence interval = 1.151–3.836, P = 0.016). The pancreas was the main site of infection, followed by lung, bloodstream and urinary tract. Klebsiella pneumoniae and Acinetobacter baumannii were the main pathogenic bacteria of CRO strains with extensive antibiotic resistance (> 60%) to 6 of 8 common antibiotics, except sulfamethoxazole (56.3%) and tigecycline (33.2%).ConclusionCRO infection has become a serious threat for CAP patients, with high rates of mortality. Procalcitonin and lactic acid represent two independent risk factors for mortality in CAP patients with CRO infection. Klebsiella pneumoniae and Acinetobacter baumannii are the primary categories of CRO pathogens. Greater efforts are needed for early prevention and prompt treatment of CRO infections in CAP patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00624-w.

704 Ceftazidime / Avibactam Efficacy for Treating Carbapenem-resistant Infections in Critically Ill Patients with Thermal Injuries

IntroductionRising antimicrobial resistance is a pressing public health concern. Emergence of carbapenem-resistant organisms has led to increased use of novel antibiotics, such as ceftazidime/avibactam (CZ/AV). However, recent studies have shown increasing treatment failures and resistance rates associated with ceftazidime/avibactam use. The efficacy of CZ/AV has not been studied in patients with thermal injuries, where pharmacokinetic derangements are common and longer lengths of stay augment risk of requiring several antimicrobial courses, leading to higher resistance rates. The objective of this study was to evaluate the outcomes of patients with thermal injuries including clinical success, the frequency of adverse effects, and emergence of resistance.MethodsThe design was a retrospective chart review. Patients were included if admitted with thermal injuries and receiving at least 48 hours of CZ/AV between Jan. 1, 2017 and July 2020. Demographics and treatment data were reported using descriptive statistics. Treatment success, description of treatment failures, and adverse events were described. Logistic regression was used to control and analyze failures.ResultsFifteen patients with 17 courses evaluated. Most were male (87 %) and African American (53 %). The mean age and weight was 47.7 ±13.6 and 96.3 ± 29.4. Seventy-three percent had a flame injury. Mean TBSA was 34 ± 18.7. Twenty percent had an inhalation injury and 80 % a significant substance use history. Clinical success occurred in 65% (11/17) although 29% died. E. cloacae (88%) was the most common treated pathogen, but 81% were polymicrobial. The most common sources were wounds (29%), blood (29%), and lungs (26%). Median days until CZ/AV initiation was 32 (14,76). CZ/AV was dosed at 2.5 g every 8 hours in all courses. Median treatment duration was 12 days (9,14). Fifty-three percent received CVVH with a mean delivered dose of 47.6 ± 9.5 ml/kg/hr. Resistance developed in 19% (3/17) of courses, but follow up sensitivities were rarely available. Logistic regression did not reveal any variables significantly associated with failure. There were no adverse events attributed to CA/AVConclusionsAlthough lower than desired, clinical success rates in this sample were similar to other reported populations treated with CZ/AV. However, the emergence of resistance occurred more frequently, and was likely underreported in this sample. HVHF did not contribute to failure, but CZ/AV was aggressively dosed in this cohort.

Prevalence of carbapenem resistance and its potential association with antimicrobial use in humans and animals in rural communities in Vietnam.

BackgroundVietnam and Southeast Asia are hotspots for antimicrobial resistance; however, little is known on the prevalence of carriage of carbapenem resistance in non-hospitalized humans and in animals. Carbapenem-resistant Enterobacteriaceae (CRE), particularly Escherichia coli (CREC) and Klebsiella pneumoniae (CRKP) and also Acinetobacter baumannii (CRAB) are emerging threats worldwide.MethodsWe investigated healthy humans (n = 652), chickens (n = 237), ducks (n = 150) and pigs (n = 143) in 400 small-scale farms in the Mekong Delta of Vietnam. Samples (rectal swabs, faecal swabs) were investigated for carriage of CRE/CRAB and were further characterized phenotypically and genotypically.ResultsIn the Mekong Delta of Vietnam, the prevalence of CRE isolates in human rectal swabs was 0.6%, including 4 CREC and 1 CRKP. One pig was infected with CREC (prevalence 0.7%). CRAB was isolated from chickens (n = 4) (prevalence 2.1%) and one duck (prevalence 0.7%). CRKP was isolated from a human who was also colonized with CREC. The CRKP strain (ST16), from an 80 year-old person with pneumonia under antimicrobial treatment, genetically clustered with clinical strains isolated in a hospital outbreak in southern Vietnam. The prevalence of CRE was higher among humans that had used antimicrobials within 90 days of the sampling date than those had not (4.2% versus 0.2%) (P = 0.005). All CRE/CRAB strains were MDR, although they were susceptible to colistin and neomycin. The carbapenemase genes identified in study strains were blaNDM and blaOXA.ConclusionsThe finding of a CRKP strain clustering with previous hospital outbreak raises concerns about potential transmission of carbapenem-resistant organisms from hospital to community settings or vice-versa.

Effectiveness of a double-carbapenem combinations against carbapenem-resistant Gram-negative bacteria

The emergence of carbapenem-resistant organisms posed considerable threat to global health while only limited treatment options are available and led to efforts to discover a novel way to treat them. To evaluate in vitro synergistic activity of meropenem plus ertapenem, a total of 203 carbapenem-resistant strains, collected from 12 provinces and municipalities in China, were examined with a dual carbapenem combination therapy. The statistical software R was used for analysis. Two hundred and one (201) of carbapenem-resistant strains mainly produced four types of carbapenemase: KPC-2 (n = 142, 69.95%), OXA-232 (n = 7, 3.45%), NDM (n = 38, 18.72%; 36 NDM-1, 1 NDM-4, 1 NDM-5), and IMP (n = 15, 7.39%; 1 IMP-26, 10 IMP-30, 4 IMP-4). Fifty-one out of two hundred and three (51/203 or 25.12%) of the examined strains showed a synergistic effect for the meropenem plus ertapenem combination throughout the checkerboard method, while only three isolates showed potential clinically relevant synergy (3/203, 1.48%). An additive effect was observed in 55/203 (27.09%) of the examined strains. Ninety-seven of the examined isolates (47.78%) showed fractional inhibitory concentration (FIC) greater or equal to 2 (indicating antagonism). The synergistic activity of meropenem plus ertapenem combination suggests this combination can be a possible way to treat the infection caused by the carbapenem-resistant organisms, especially for IMP or NDM producer with a lesser minimum inhibitory concentration (MIC) and the infected individual who was not recommended to use colistin or tigecycline.

Molecular Characterization of Carbapenem-Resistant Enterobacterales Collected in the United States.

Carbapenem-resistant Enterobacterales (CRE) are a growing public health concern due to resistance to multiple antibiotics and potential to cause health care-associated infections with high mortality. Carbapenemase-producing CRE are of particular concern given that carbapenemase-encoding genes often are located on mobile genetic elements that may spread between different organisms and species. In this study, we performed phenotypic and genotypic characterization of CRE collected at eight U.S. sites participating in active population- and laboratory-based surveillance of carbapenem-resistant organisms. Among 421 CRE tested, the majority were isolated from urine (n = 349, 83%). Klebsiella pneumoniae was the most common organism (n = 265, 63%), followed by Enterobacter cloacae complex (n = 77, 18%) and Escherichia coli (n = 50, 12%). Of 419 isolates analyzed by whole genome sequencing, 307 (73%) harbored a carbapenemase gene; variants of blaKPC predominated (n = 299, 97%). The occurrence of carbapenemase-producing K. pneumoniae, E. cloacae complex, and E. coli varied by region; the predominant sequence type within each genus was ST258, ST171, and ST131, respectively. None of the carbapenemase-producing CRE isolates displayed resistance to all antimicrobials tested; susceptibility to amikacin and tigecycline was generally retained.

Incidence and All-Cause Mortality Rates in Neonates Infected With Carbapenem Resistant Organisms

IntroductionMultidrug-resistant, Gram-negative infections, particularly due to carbapenem resistant organisms (CRO), have increased globally. Few studies have reported on the burden of CRO in neonates from low-middle income countries (LMIC). This study aimed to determine the incidence and mortality rates of culture-confirmed Gram-negative infections, with a special focus on CRO in a neonatal unit from a LMIC.Materials and MethodsPositive bacterial cultures from sterile sites of infants admitted in the neonatal unit from the 1st January 2018 to 31st December 2019, were reviewed retrospectively. Type of organism, susceptibility and outcomes were recorded. Data on Gram-negative isolates, including the CRO, were extracted. Rates and outcomes were analysed.ResultsThere were 2219 neonates with organisms isolated from sterile sites (blood and cerebrospinal fluid), accounting for 30% of all admissions, giving a neonatal sepsis incidence of 17.9/1000 patient-days. There was a total of 1746 positive isolates (excluding coagulase negative Staphyloccocus). Of these, 1706 (98%) were isolated from blood, and 40 (2%) from cerebrospinal fluid. Overall, 1188 (68%) were Gram-negative, 371 (21%) Gram-positive and 187 (10.7%) fungal isolates. The common Gram-negatives were Acinetobacter baumannii (526/1188;44%) and Klebsiella pneumoniae (469/1188;40%). Carbapenem resistance was observed in 359 (68%) of the Acinetobacter baumannii (CRAB) and in 103 (18%) of the Enterobacterales (CRE) isolates, with 98% of CRE being Klebsiella pneumoniae (CR-Klebs). Twenty-four (41%) of Pseudomonas species were carbapenem resistant. Overall, carbapenem resistance was seen in 42% of all Gram-negative organisms. The rate of CRAB and CRE were 2.9 and 0.8/1000 patient-days respectively. The overall, all-cause in-hospital mortality rate in infants with Gram-negative isolates was 22%, with higher mortality rate in those infected with CRO compared to non-CRO (34% vs 13%; OR 3.44; 95% CI 2.58–4.60; p &amp;lt; 0.001). The mortality rate in infants with CRE was higher than those with CRAB (48% vs 33%; OR 1.85; 95% CI 1.18–2.89; p = 0.007).ConclusionWe observed a high incidence of positive cultures from sterile sites. The common organisms isolated were Gram-negatives, and among these carbapenem resistance was high and was associated with high mortality. Mortality was higher in infants with CRE compared to those with CRAB.