Donor-derived carbapenem-resistant gram-negative bacterial infections in solid organ transplant recipients: Active surveillance enhances recipient safety.

Donor-derived infections (DDIs) caused by carbapenem-resistant gram-negative bacteria (CR-GNB) in solid organ transplant recipients are potentially life-threatening. In this prospective study, we evaluated the incidence, factors associated with transmission, and the outcome of recipients with unexpected CR-GNB DDIs after the implementation of our local active surveillance system (LASS). LASS provides for early detection of unexpected donor CR-GNB infections, prophylaxis of recipients at high risk, and early diagnosis and treatment of DDIs. Whole genome sequencing confirmed DDI. Among 791 recipients, 38 (4.8%) were at high risk of unexpected CR-GNB DDI: 25 for carbapenem-resistant Enterobacterales (CRE) and 13 for carbapenem-resistant Acinetobacter baumannii (CRAB). Transmission did not occur in 27 (71%) cases, whereas DDIs occurred in 9 of 25 of CRE and 2 of 13 of CRAB cases. Incidence of CR-GNB DDI was 1.4%. Recipients of organs with CR-GNB-positive preservation fluid and liver recipients from a donor with CRE infection were at the highest risk of DDI. There was no difference in length of hospital stay or survival in patients with and without CR-GNB DDI. Our LASS contains transmission and mitigates the negative impacts of CR-GNB DDI. Under well-defined conditions, organs from donors with CR-GNB may be considered after a thorough evaluation of the risk/benefit profile.

Carbapenem-resistant gram-negative bacterial infections and risk factors for acquisition in a Kenyan intensive care unit.

BACKGROUND: Carbapenem-resistant Gram-negative bacteria (CR-GNB) are a critical public health threat globally; however, there are inadequate surveillance data, especially in intensive care units (ICU), to inform infection prevention and control in many resource-constrained settings. Here, we assessed the prevalence of CR-GNB infections and risk factors for acquisition in a Kenyan ICU. METHODS: A hospital-based cross-sectional study design was adopted, recruiting 162 patients clinically presenting with bacterial infection after 48 h of ICU admission, from January to October 2022 at the Nairobi West Hospital, Kenya. Demographics and clinical data were collected by case report form. The type of sample collected, including blood, tracheal aspirate, ascitic tap, urine, stool, and sputum depended on the patient's clinical presentation and were transported to the hospital Microbiology laboratory in a cool box for processing within 2 h. The samples were analyzed by cultured and BD Phoenix system used for isolates' identity and antimicrobial susceptibility. RESULTS: CR-GNB infections prevalence was 25.9% (42/162), with Klebsiella pneumoniae (35.7%, 15/42) and Pseudomonas aeruginosa (26.2%, 11/42) predominating. All isolates were multidrug-resistant (MDR). P. aeruginosa and A. baumannii were 100% colistin-resistant, while K. pneumoniae (33.3%) was tigecycline-resistant. History of antibiotics (aOR = 3.40, p = 0.005) and nasogastric tube (NGT) use (aOR = 5.84, p = < 0.001) were the risk factors for infection. CONCLUSION: Our study highlights high MDR- and CR-GNB infections in ICU, with prior antibiotic exposure and NGT use as risk factors, and diminishing clinical value of colistin and tigecycline. In this study setting and beyond, strict implementation of antimicrobial stewardship programs and adherence to infection prevention and control through monitoring, evaluation and feedback are warranted to curb CR-GNB infections, especially among the risk groups.

Prediction of carbapenem-resistant gram-negative bacterial bloodstream infection in intensive care unit based on machine learning.

BACKGROUND: Predicting whether Carbapenem-Resistant Gram-Negative Bacterial (CRGNB) cause bloodstream infection when giving advice may guide the use of antibiotics because it takes 2-5 days conventionally to return the results from doctor's order. METHODS: It is a regional multi-center retrospective study in which patients with suspected bloodstream infections were divided into a positive and negative culture group. According to the positive results, patients were divided into the CRGNB group and other groups. We used the machine learning algorithm to predict whether the blood culture was positive and whether the pathogen was CRGNB once giving the order of blood culture. RESULTS: There were 952 patients with positive blood cultures, 418 patients in the CRGNB group, 534 in the non-CRGNB group, and 1422 with negative blood cultures. Mechanical ventilation, invasive catheterization, and carbapenem use history were the main high-risk factors for CRGNB bloodstream infection. The random forest model has the best prediction ability, with AUROC being 0.86, followed by the XGBoost prediction model in bloodstream infection prediction. In the CRGNB prediction model analysis, the SVM and random forest model have higher area under the receiver operating characteristic curves, which are 0.88 and 0.87, respectively. CONCLUSIONS: The machine learning algorithm can accurately predict the occurrence of ICU-acquired bloodstream infection and identify whether CRGNB causes it once giving the order of blood culture.

Clinical efficacy of renal dosing adjustments of ceftazidime-avibactam in patients affected by carbapenem-resistant Gram-negative infections: A systematic review and meta-analysis of observational studies.

AIMS: The aim of this study is to assess clinical efficacy of ceftazidime-avibactam for the management of carbapenem-resistant Gram-negative infections in renal patients receiving recommended dosing adjustments compared to those treated with scheduled full-dose. METHODS: Two authors independently searched PubMed-MEDLINE and Scopus database from inception to 31 December 2021, to retrieve randomized controlled trials or observational studies comparing clinical efficacy of ceftazidime-avibactam in patients affected by carbapenem-resistant Gram-negative infections receiving recommended renal dosing adjustments compared to those treated with scheduled full-dose. Data were independently extracted by the 2 authors, and the quality of included studies was independently assessed according to ROBINS-I tool for observational studies. Mortality rate was selected as primary outcome. Meta-analysis was conducted by including only studies at low or moderate risk of bias providing adjustment for confounders. RESULTS: In total, 1794 articles were screened, and 11 observational studies (1 prospective and 10 retrospective) were included. Serious or critical risk of bias was found in 4 studies, while the other 7 were classified at moderate risk of bias and included in the meta-analysis. Renal dosing adjustments of ceftazidime-avibactam were associated with higher risk of mortality (odds ratio 1.79; 95% confidence interval 1.18-2.72). CONCLUSION: Renal dosing adjustment of ceftazidime-avibactam seems to be associated with a higher risk of mortality in patients affected by carbapenem-resistant Gram-negative infections. However, residual confounder associated with baseline conditions cannot be excluded. Further prospective studies including larger samples are warranted to definitively address this unmet clinical need.

Ceftazidime/avibactam combined with colistin: a novel attempt to treat carbapenem-resistant Gram-negative bacilli infection.

BACKGROUND: The rapid global emergence and spread of carbapenem-resistant Gram-negative bacilli (CR-GNB) is recognized as a major public health concern, and there are currently few effective treatments for CR-GNB infection. The aim of this study was to investigate the clinical characteristics and outcomes of patients with CR-GNB infections treated with ceftazidime/avibactam (CAZ/AVI) combined with colistin from October 2019 to February 2023 in China. METHODS: A total of 31 patients with CR-GNB infections were retrospectively identified using the electronic medical record system of Zhejiang Provincial People's Hospital. RESULTS: Thirty-one patients were treated with CAZ/AVI combined with colistin. Respiratory tract infections (87%) were most common. The common drug-resistant bacteria encompass Klebsiella pneumonia (54.8%), Acinetobacter baumannii (29.0%), and Pseudomonas aeruginosa (16.1%). The 30-day mortality rate was 29.0%, and the 7-day microbial clearance rate was 64.5%. The inflammatory marker CRP changes, but not PCT and WBC, were statistically significant on days 7 and 14 after combination therapy. There were seven patients developing acute renal injury (AKI) after combination therapy and treating with continuous renal replacement therapy (CRRT). Two patients developed diarrhea. CONCLUSION: The combination of CAZ/AVI and colistin has potential efficacy in patients with CR-GNB infection, but more studies are needed to determine whether it can reduce 30-day mortality rates and increase 7-day microbial clearance. At the same time, the adverse reactions of combination therapy should not be ignored.

Polymyxin B therapy based on therapeutic drug monitoring in carbapenem-resistant organisms sepsis: the PMB-CROS randomized clinical trial.

BACKGROUND: The appropriate administration regimen of polymyxin B is yet controversial. The present study aimed to explore the optimal dose of polymyxin B under therapeutic drug monitoring (TDM) guidance. METHODS: In China's Henan province, 26 hospitals participated in a randomized controlled trial. We included patients with sepsis caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) susceptible to polymyxin B. The patients were randomly divided into a high-dose (HD) group or a low-dose (LD) group and received 150 mg loading dose, 75 mg every 12 h and 100 mg loading dose, 50 mg every 12 h, respectively. TDM was employed to determine if the dose of polymyxin B needs adjustment based on the area under the concentration-time curve across 24 h at a steady state (ssAUC0-24) of 50-100 mg h/L. The primary outcome was the 14-day clinical response, and the secondary outcomes included 28- and 14-day mortality. RESULTS: This trial included 311 patients, with 152 assigned to the HD group and 159 assigned to the LD group. Intention-to-treat analysis showed that the 14-day clinical response was non-significant (p = 0.527): 95/152 (62.5%) in the HD group and 95/159 (59.7%) in the LD group. Kaplan-Meier's 180-day survival curve showed survival advantage in the HD group than in the LD group (p = 0.037). More patients achieved the target ssAUC0-24 in the HD than in the LD group (63.8% vs. 38.9%; p = 0.005) and in the septic shock subgroup compared to all subjects (HD group: 71.4% vs. 63.8%, p = 0.037; LD group: 58.3% vs. 38.9%, p = 0.0005). Also, the target AUC compliance was not correlated with clinical outcomes but with acute kidney injury (AKI) (p = 0.019). Adverse events did not differ between the HD and LD groups. CONCLUSION: A fixed polymyxin B loading dose of 150 mg and a maintenance dose of 75 mg every 12 h was safe for patients with sepsis caused by CR-GNB and improves long-term survival. The increased AUC was associated with increased incidence of AKI, and TDM results were valued to prevent AKI. Trial registration Trial registration ClinicalTrials.gov: ChiCTR2100043208, Registration date: January 26, 2021.

Carbapenem-resistant gram-negative bacteria in Germany: incidence and distribution among specific infections and mortality: an epidemiological analysis using real-world data.

PURPOSE: Infections with carbapenem-resistant gram-negative bacteria (in Germany classified as 4MRGN) are a growing threat in clinical care. This study was undertaken to understand the overall burden of 4MRGN infections in Germany in the context of a Health Technology Appraisal (HTA) for Ceftazidime/Avibactam (CAZ/AVI). Besides, the incidences mortality was an endpoint of interest. METHODS: To assess infections with carbapenem-resistant gram-negative bacteria and related mortality, three different data sources have been used. From the German statistics office (DESTATIS) data have been retrieved to obtain the overall frequency these pathogens. Via two other databases, the German analysis database (DADB) and a Benchmarking of > 200 hospitals in a representative sample (BM-DB), the distribution of the infections and the mortality have been analyzed. RESULTS: DESTATIS data showed a total of 11,863 carbapenem-resistant gram-negative bacteria codings, of which 10,348 represent infections and 1515 carriers. The most frequent infections were complicated urinary tract infections (cUTI) (n = 2,337), followed by pneumonia (n = 1006) and intra-abdominal infections (n = 730). A considerable amount of patients had multiple infections in one hospital episode (n = 1258). In-hospital mortality was 18.6% in DADB and 14.3% in the BM-DB population, respectively. In cases with additional bloodstream infections, DADB mortality was correspondingly higher at 33.0%. DADB data showed an incremental mortality increase of 5.7% after 30 days and 10.0% after 90 days resulting in a cumulative 90 day mortality of 34.3%. CONCLUSIONS: Infections with carbapenem-resistant gram-negative bacteria are still rare (6.8-12.4 per 100,000) but show a significant increase in mortality compared to infections with more sensitive pathogens. Using different data sources allowed obtaining a realistic picture.

Clinical outcomes and safety of polymyxin B in the treatment of carbapenem-resistant Gram-negative bacterial infections: a real-world multicenter study.

BACKGROUND: High morbidity and mortality due to carbapenem-resistant Gram-negative bacilli (CR-GNB) has led to the resurgence of polymyxin B (PMB) use in the last decade. The aim of our multicenter, real-world study was to evaluate the effectiveness and safety of PMB in the treatment of CR-GNB infections. METHODS: The real-world study included patients treated with intravenous PMB for at least 7 days during the period of October 2018 through June 2019. Associations between these clinical features and 28-day mortality or all-cause hospital mortality were explored through univariate analyses and multivariable logistic regression. RESULTS: The study included 100 patients. Many patients presented with combined chronic conditions, septic shock, mechanical ventilation, and the presence of Klebsiella pneumoniae. The mean duration of PMB therapy was 11 days (range 7-38 days). Temperature (38 °C vs 37.1 °C), white blood cells (14.13 × 109/l vs 9.28 × 109/l), C-reactive protein (103.55 ug/l vs 47.60 ug/l), procalcitonin (3.89 ng/ml vs 1.70 ng/ml) and APACHE II levels (17.75 ± 7.69 vs 15.98 ± 7.95) were significantly decreased after PMB treatment. The bacteria eradication rate was 77.65%. The overall mortality at discharge was 15%, and 28-day mortality was 40%. Major adverse reactions occurred in 16 patients. Nephrotoxicity was observed in 7 patients (7%). CONCLUSIONS: Our results provide positive clinical and safety outcomes for PMB in the treatment of CR-GNB. Timely and appropriate use of PMB may be particularly useful in treating patients with sepsis in CR-GNB infections.

Efficacy and safety of polymyxin B in carbapenem-resistant gram-negative organisms infections.

OBJECTIVE: To investigate how to use polymyxin B rationally in order to produce the best efficacy and safety in patients with carbapenem-resistant gram-negative organisms (CRO) infection. METHODS: The clinical characteristics and microbiological results of 181 patients caused by CRO infection treated with polymyxin B in the First Affiliated Hospital from July 2018 to May 2020 were retrospectively analyzed. The bacterial clearance rate, clinical efficacy, adverse drug reactions and 28 days mortality were evaluated. RESULTS: The overall effective rate of 181 patients was 49.72%, the total bacterial clearance rate was 42.0%, and the 28 day all-cause mortality rate was 59.1%. The effective rate and bacterial clearance rate in the group of less than 24 h from the isolation of CRO to the use of polymyxin B were significantly higher than those in the group of more than 24 h. Logistics multivariate regression analysis showed that the predictive factors for effective treatment of CRO with polymyxin B were APACHEII score, duration of polymyxin B treatment, combination of polymyxin B and other antibiotics, and bacterial clearance. 17 cases (9.36%) of acute kidney injury were considered as polymyxin B nephrotoxicity and 4 cases (23.5%) recovered after polymyxin B withdrawal. After 14 days of polymyxin B use, 3 cases of polymyxin B resistance appeared, and there were 2 cases of polymyxin B resistance in the daily dose 1.5 mg/kg/day group. CONCLUSION: For CRO infection, the treatment of polymyxin B should be early, combined, optimal dose and duration of treatment, which can achieve better clinical efficacy and microbial reactions, and reduce the adverse reactions and drug resistance.

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

BACKGROUND: Effective 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. METHODS: We 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. RESULTS: A 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. CONCLUSION: The 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.

Effectiveness of tigecycline in the treatment of infections caused by carbapenem-resistant gram-negative bacteria in pediatric liver transplant recipients: A retrospective study.

INTRODUCTION: Tigecycline (TGC) is effective for the infections caused by carbapenem-resistant gram-negative bacteria (CRGNB) in adults, but it is not investigated systematically in children because of concern about adverse effects. This study aimed to analyze the effectiveness of TGC in treating CRGNB infections in children after receiving liver transplant. METHODS: The subjects in this retrospective study were pediatric liver transplant recipients treated with TGC for at least 3 days to fight microbiologically verified CRGNB infection after initial antibiotic failure during the period from January 2014 to May 2018. Clinical and microbiological outcomes were reviewed to evaluate the efficacy and safety of TGC. RESULTS: Of the 1177 pediatric liver transplant recipients, 13 patients were eligible for inclusion in this analysis. All the patients received TGC at dose of 2 mg/kg every 12 hours for a duration of 10.1 ± 5.1 days on average to treat CRGNB infections, including complicated intra-abdominal infection, ventilator-associated pneumonia, and bloodstream infection. The isolates included Klebsiella pneumoniae (69.2%, 9/13) and Acinetobacter baumannii (30.8%, 4/13). Clinical efficacy was achieved in 84.6% (11/13) and pathogen eradicated in 69.2% (9/13) of the patients. The overall mortality rate was 15.4% (2/13). No TGC-related serious adverse event was reported. CONCLUSION: Tigecycline can be considered in combination antimicrobial regimen for treating CRGNB-related infections in pediatric liver transplant recipients.

Impact of Preemptive Granulocyte Infusions During Febrile Neutropenia in Patients Colonized with Carbapenem-Resistant Gram-Negative Bacteria Undergoing Haploidentical Transplantation.

We prospectively studied the impact of preemptive granulocyte infusions (pGIs) in 69 patients colonized with carbapenem-resistant gram-negative bacteria (CRGNB) undergoing haploidentical hematopoietic cell transplantation (HCT) compared with a previous cohort of 33 patients who received only antimicrobials directed toward CRGNB at the onset of neutropenic fever (non-pGI group). All patients developed neutropenic fever at a median of day +8 (range, -4 to +12) after transplantation. Engraftment kinetics were similar for both groups. The median number of GIs was 2 (range, 1 to 7), and the median dose of granulocytes infused was 5 × 1010 granulocytes per infusion (range, 1 to 30). The overall incidence of CRGNB bloodstream infections (BSIs) was 21.2% in non-pGI group (7/33) and 17.5% (12/69) in the pGI group (P = .8). However, the CRGNB-related mortality among those with BSI was 100% (7/7) in the non-pGI group versus 16.6% (2/12) in the pGI group (P = .001). The day 100 (4.4% versus 24.4%, P = .002) and 2-year nonrelapse mortality (7.5% versus 35.6%, P = .0001) were significantly reduced in the pGI group. The overall survival at 2 years was 75.6% in the pGI group versus 21.2% in the non-pGI group (P = .0001). Colonization and subsequent BSI with CRGNB are associated with a high incidence of mortality in patients undergoing HCT. pGI reduced early mortality associated with CRGNB in colonized patients undergoing post-transplant cyclophosphamide-based haploidentical HCT.

Resistance reported from China antimicrobial surveillance network (CHINET) in 2018.

The aim of this study is to investigate the antimicrobial susceptibility of strains isolated from the major hospitals in China. A total of 44 teaching hospitals were involved. Antimicrobial susceptibility testing was conducted by Kirby-Bauer automated systems, and results were interpreted using CLSI criteria. Totally 244,843 strains were isolated in 2018, of which gram-negative bacilli and gram-positive cocci were accounting for 71.8% and 28.2%, respectively. 39.7% of isolates were cultured from lower respiratory tract, 18.8% from urine, 14.8% from blood, 1.3% from cerebrospinal fluid, respectively. Of those, the five major species were most often isolated (65.5%, 63%, 52.3%, and 30.3%). The resistance rate of MRSA to most antimicrobial agents was significantly higher than that of MSSA strains, except for to trimethoprim-sulfamethoxazole in urine specimen. E.coli was still highly susceptible to carbapenem antibiotics, and the resistance rate was less than 5%. Carbapenem resistance among Klebsiella pneumoniae, especially cultured from cerebrospinal fluid, increased significance from 18.6 to 64.1%. The resistance rates of Pseudomonas aeruginosa to carbapenems were nearly 30% in the blood, in urine, and in the lower respiratory tract, but about 60% of that in cerebrospinal fluid. About 80% of Acinetobacter baumannii strains was resistant to imipenem and meropenem, respectively. Bacterial resistance of five major clinical isolates from cerebrospinal fluid to common antibiotics (in particular Carbapenem-resistant Klebsiella pneumoniae) currently shows an increasing trend. It is worth to emphasize the importance of serious control of hospital infection and better management of clinical use of antimicrobial agents.

Assessment of a newly developed immunochromatographic assay for NDM-type metallo-ß-lactamase producing Gram-negative pathogens in Myanmar.

BACKGROUND: To detect carbapenemase-producing Gram-negative bacteria in bacterial laboratories at medical settings, a new immunochromatographic assay for New Delhi metallo-ß-lactamases (NDMs) was developed. METHODS: The immunochromatographic assay for New Delhi metallo-ß-lactamases producers was developed using rat monoclonal antibodies against NDMs. The assessment was performed using 350 isolates of Gram-negative bacteria, including Acinetobacter baumannii (51 isolates), Enterobacteriaceae (163 isolates), and Pseudomonas aeruginosa (136 isolates) obtained from 2015 to 2017 in medical settings in Myanmar. Of them, 302 isolates were resistant to carbapenems, including imipenem and/or meropenem. The blaNDM genes were identified by PCR and sequencing. RESULTS: Of the 350 clinical isolates tested, 164 (46.9%) (60 isolates of Escherichia coli, 51 isolates of Klebsiella pneumoniae, 25 isolates of Enterobacter cloacae, 23 isolates of P. aeruginosa, and 5 isolates of A. baumannii) were positive on this assay, and all the positive isolates harbored genes encoding NDM-1, - 4, - 5 and - 7. The remaining 186 (53.1%) isolates negative on the assay did not harbor genes encoding NDMs. The assay had a specificity of 100% and a sensitivity of 100%. The assessment revealed that more than 90% of carbapenem-resistant Enterobacteriaceae produced NDMs. CONCLUSIONS: The immunochromatographic assay is an easy-to-use and reliable kit for detection of NDMs-producing Gram-negative bacteria. The assay revealed that NDM-producing Enterobacteriaceae isolates are wide-spread in medical settings in Myanmar.

Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial.

BACKGROUND: Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. METHODS: A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7-14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. RESULTS: A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of - 2.16 (- 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015). CONCLUSIONS: This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01292031. Registered 9 February 2011.

Microbial infection pattern, pathogenic features and resistance mechanism of carbapenem-resistant Gram negative bacilli during long-term hospitalization.

BACKGROUND: Carbapenem-resistant Gram-negative bacilli (GNB) have become an important cause of nosocomial infections of hospitalized patients. METHODS: To investigate the microbial infection patterns and molecular epidemiology characteristics of the carbapenem-resistant GNB isolates from a long-term hospitalized patient, antimicrobial susceptibility testing, phenotypic screening test for carbapenemase production, PCR screening and DNA sequencing of carbapenemase genes, repetitive extragenic palindromic sequence-based PCR (REP-PCR), multilocus sequencing typing (MLST) and genetic environment analysis were performed. RESULTS: Twelve strains with carbapenemase genes were detected from 63 carbapenem-resistant isolates, including two blaIMP-25-carrying Pseudomonas aeruginosa, one blaNDM-1-carrying Citrobacter freundii, three blaNDM-1-carrying Klebsiella pneumoniae and six blaKPC-2-carrying K. pneumoniae. Only the blaNDM-1 genes were successfully transferred from three K. pneumoniae strains to Escherichia coli C600 by conjugation. Genetic environment of blaIMP-25, blaNDM-1 and blaKPC-2 genes in our study were consistent with previous reports. Molecular typing of K. pneumoniae performed by MLST revealed that most of the isolates belonged to ST11. blaNDM-1-carrying K. pneumoniae sequencing type 1416 was first reported in our study. CONCLUSIONS: Carbapenem-resistant GNB are common pathogens during long-term hospitalization, and ST11 blaKPC-2-carrying K. pneumoniae is the dominant bacterium in our study. Colonization and horizontal transmission of resistance by plasmids of carbapenem-resistant GNB have increased the risks of persistent infection and mortality of long-term hospitalized patients.

The evaluation of safety and efficacy of colistin use in pediatric intensive care unit: Results from two reference hospitals and review of literature.

Colistin, an old cationic polypeptide antibiotic, have been reused due to rising incidence of infections caused by multi-drug resistant (MDR) Gram-negative microorganisms and the lack of new antibiotics. Therefore, we evaluated safety and efficacy of colistin in treatment of these infections. This study included 104 critically ill children with a median age of 55,9 months between January 2011 and January 2016. Nephrotoxicity occurred in 11 (10.5%) patients. Nephrotoxicity occurred between the third and seventh day of treatment in 63% of colistin induced nephrotoxicity episodes. The subgroup analysis between the patients who developed nephrotoxicity during colistin treatment and those that did not, showed no significant difference in terms of age, underlying disease, cause for PICU admission and type of infection required colistin treatment, P values were 0.615, 0.762, 0.621, 0.803, respectively. All patients were receiving a concomitant nephrotoxic agent (P = 0,355). The majority of the patients (52%) were having primary or secondary immune deficiency in treatment failure group and the most common cause of PICU admission was sepsis in treatment failure group, P values were 0.007 and 0.045, respectively. Mortality attributed to colistin failure and crude mortality were 14.4% and 29.8%, respectively. In conclusion, colistin may have a role in the treatment of infections caused by multidrug-resistant Gram-negative bacteria in critically ill children. However, the patients have to be followed for side effects throughout colistin treatment, not for only early stage. And the clinicians should be aware of increase in the rate of nephrotoxicity in patients those have been receiving a concomitant nephrotoxic agent.

Epidemiological surveillance of multidrug-resistant gram-negative bacteria in a solid organ transplantation department.

BACKGROUND: We assessed the impact of intensified infection control measures (ICM) on colonization and infection caused by carbapenem-resistant (CR) Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii in a solid organ transplantation (SOT) department. METHODS: A quasi-experimental methodology was followed. The study was divided into three periods: pre-intervention, intervention with implementation of an ICM bundle including active surveillance program (ASP) and gradually enhanced measures, and post-ASP without ASP. The bundle included active surveillance cultures, contact precautions, hand hygiene, education of health care workers (HCWs), monitoring of compliance, and environmental cleaning. Incidence of colonization and infection caused by CR gram-negative bacteria was recorded. Molecular analysis of CR bacteria was performed for a certain period. RESULTS: During the intervention, incidence of colonization reduced from 19% to 9% (P<.001). The compliance of HCWs with contact precautions and hand hygiene also improved. Monthly incidence of infections caused by these CR bacteria increased from 2.8 to 6.9/1000 bed-days (P<.001). However, this increase did not have such a strong trend after the intervention. Most K. pneumoniae isolates, the commonest pathogen, carried the blaKPC gene. Colonization and infection rates by CR K. pneumoniae, P. aeruginosa, and A. baumannii were high among SOT recipients. CONCLUSION: In settings where CR gram-negative bacteria are endemic, colonization and infection rates by these bacteria are high among SOT recipients. Implementation of enhanced ICM in all related units of a hospital, although challenging, reduces colonization rates by CR gram-negative bacteria.

Carbapenem resistant Gram-negative bacteremia in an Indian intensive care unit: A review of the clinical profile and treatment outcome of 50 patients.

BACKGROUND: Growing antimicrobial resistance and limited therapeutic options to treat carbapenem-resistant bacteremia prompted us to evaluate the clinical outcomes associated with healthcare-associated bacteremia. METHODS: This was a retrospective observational study of carbapenem-resistant Gram-negative bacteremia performed at a tertiary care facility in Chennai, India between May 2011 and May 2012. RESULTS: In our study, patients had mean 11.76 days of intensive care unit (ICU) care and mean time to onset of bacteremia was 6.4 days after admission. The commonest organism was Klebsiella pneumoniae (44%). Patients with combination treatment had lower mortality (44.8%) compared with colistin monotherapy (66.6%); (P = 0.35). CONCLUSION: Carbapenem resistant bacteremia is a late onset infection in patients with antibiotic exposure in the ICU and carries a 30 days mortality of 60%; K. pneumoniae is the most common organism at our center. Two drug combinations appear to carry a lower mortality compared with monotherapy.