Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice

ObjectivesNovel therapeutics are urgently required for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) causing critical infections with high mortality. Here we assessed the therapeutic potential of the clinical-stage drug candidate EBL-1003 (crystalline free base of apramycin) in the treatment of CRAB lung infections.MethodsThe genotypic and phenotypic susceptibility of CRAB clinical isolates to aminoglycosides and colistin was assessed by database mining and broth microdilution. The therapeutic potential was assessed by target attainment simulations on the basis of time–kill kinetics, a murine lung infection model, comparative pharmacokinetic analysis in plasma, epithelial lining fluid (ELF) and lung tissue, and pharmacokinetic/pharmacodynamic (PKPD) modelling.ResultsResistance gene annotations of 5451 CRAB genomes deposited in the National Database of Antibiotic Resistant Organisms (NDARO) suggested >99.9% of genotypic susceptibility to apramycin. Low susceptibility to standard-of-care aminoglycosides and high susceptibility to EBL-1003 were confirmed by antimicrobial susceptibility testing of 100 A. baumannii isolates. Time–kill experiments and a mouse lung infection model with the extremely drug-resistant CRAB strain AR Bank #0282 resulted in rapid 4-log CFU reduction both in vitro and in vivo. A single dose of 125 mg/kg EBL-1003 in CRAB-infected mice resulted in an AUC of 339 h × μg/mL in plasma and 299 h × μg/mL in ELF, suggesting a lung penetration of 88%. PKPD simulations suggested a previously predicted dose of 30 mg/kg in patients (creatinine clearance (CLCr) = 80 mL/min) to result in >99% probability of –2 log target attainment for MICs up to 16 μg/mL.ConclusionsThis study provides proof of concept for the efficacy of EBL-1003 in the treatment of CRAB lung infections. Broad in vitro coverage, rapid killing, potent in vivo efficacy, and a high probability of target attainment render EBL-1003 a strong therapeutic candidate for a priority pathogen for which treatment options are very limited.     

In vivo fitness of carbapenem-resistant Acinetobacter baumannii strains in murine infection is associated with treatment failure in human infections

ObjectivesMortality among patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections varies between studies. We examined whether in vivo fitness of CRAB strains is associated with clinical outcomes in patients with CRAB infections.MethodsIsolates were collected from patients enrolled in the AIDA trial with hospital-acquired pneumonia, bloodstream infections and/or urinary tract infections caused by CRAB. The primary outcome was 14-day clinical failure, defined as failure to meet all criteria: alive; haemodynamically stable; improved or stable Sequential Organ Failure Assessment (SOFA) score; improved or stable oxygenation; and microbiological cure of bacteraemia. The secondary outcome was 14-day mortality. We tested in vivo growth using a neutropenic murine thigh infection model. Fitness was defined based on the CFU count 24 hours after injection of an inoculum of 10⁵ CFU. We used mixed-effects logistic regression to test the association between fitness and the two outcomes.ResultsThe sample included 266 patients; 215 (80.8%) experienced clinical failure. CRAB fitness ranged from 5.23 to 10.08 log CFU/g. The odds of clinical failure increased by 62% for every 1-log CFU/g increase in fitness (OR 1.62, 95% CI 1.04–2.52). After adjusting for age, Charlson score, SOFA score and acquisition in the intensive care unit, fitness remained significant (adjusted OR 1.63, 95% CI 1.03–2.59). CRAB fitness had a similar effect on 14-day mortailty, although the association was not statistically significant (OR 1.56, 95% CI 0.95–2.57). It became significant after adjusting for age, Charlson score, SOFA score and recent surgery (adjusted OR 1.88, 95% CI 1.09–3.25).ConclusionsIn vivo CRAB fitness was associated with clinical failure in patients with CRAB infection.     

Clinical characteristics and outcomes of community and hospital-acquired Acinetobacter baumannii bacteremia

PurposeWe aimed to characterize clinical manifestations of the patients with bacteremia due to community-acquired Acinetobacter baumannii and evaluate the outcomes of these patients.MethodsWe conducted a retrospective study to include adult patients with A. baumannii bacteremia and then classified them into two groups: community-acquired A. baumannii bacteremia and hospital-acquired A. baumannii bacteremia. Characteristics and outcomes between 2 groups were compared. The Galleria mellonella infection survival model was used to determine the virulence of A. baumannii in these 2 groups.ResultsThere were 63 patients with A. baumannii bacteremia: 21 patients with community-acquired (CA) bacteremia and 42 patients with hospital-acquired (HA) bacteremia. Three patients with CA bacteremia were excluded due to healthcare-associated risks of infection. The remaining 18 patients with CA bacteremia had carbapenem-susceptible A. baumannii (CA-CSAB). Among the 42 patients with HA bacteremia, 11 patients had carbapenem-susceptible A. baumannii (HA-CSAB) and 31 patients had carbapenem-resistant A. baumannii (HA-CRAB). The 30-day mortality rates of those with CA-CSAB did not differ from those with HA-CSAB bacteremia but were significantly lower than those with HA-CRAB (p = 0.003). The factors influencing 30-day mortality were infection with CRAB (p = 0.004), appropriate empirical antimicrobial therapy (p = 0.002), and higher Acute Physiology and Chronic Health Evaluation II score (p < 0.001). The G. mellonella assay showed no differences in survival rates among CA-CSAB, HA-CSAB, and HA-CRAB.ConclusionsPatients with bacteremia due to CA-CSAB and HA-CSAB had similar outcomes. Similar virulences of CA-CSAB and HA-CSAB were confirmed with the G. mellonella infection model.     

Diabetic status and the relationship of blood glucose to mortality in adults with carbapenem-resistant Acinetobacter baumannii complex bacteremia

Background/PurposeDiabetes is associated with increased mortality in Acinetobacter baumannii (AB) complex infection. This study investigated the risk factors and relationship of diabetic status and glycemic indices to mortality in patients with carbapenem-resistant (CR) AB complex bacteremia.MethodsRelationship of glycemic indices to mortality were compared in adult diabetes (DM) and nondiabetes (non-DM) patients with CRAB complex bacteremia hospitalized from January 2010 to December 2015 in MacKay Memorial Hospital, Taiwan.ResultsOf 317 patients with CRAB complex bacteremia, 146 (46.06%) had diabetes. DM patients were elderly (mean age of 69.23 years) and the mortality rate was higher (64.38% vs. 52.05%, p = 0.036) than in non-DM patients. By multivariate analysis, septic shock was associated with increased mortality in DM patients. Hypoglycemia was associated with increased mortality in non-DM patients only (100% vs. 50.33%, p = 0.006). The lowest mortality was for the blood glucose range 70–100 mg/dL in non-DM patients (43.24%) and 100–140 mg/dL for DM patients (56.52%). Increased glycemic variability (coefficient of variation (CV) > 40% compared to < 20%) was associated with increased mortality in non-DM patients (86.36% vs. 47.12%, p = 0.003).ConclusionEffects of dysglycemia on mortality due to CRAB complex bacteremia differ according to diabetic status. Mortality was higher in DM patients. In non-DM patients, hypoglycemia and increased CV were associated with increased mortality. The lowest mortality was for the blood glucose range 70–100 mg/dL in non-DM patients and 100–140 mg/dL for DM patients.     

Metal nanoparticles and nanoparticle composites are effective against Haemophilus influenzae,Streptococcus pneumoniae,and multidrug-resistant bacteria

BackgroundTreatment for lower respiratory tract infection caused by multidrug-resistant organisms (MDRO) are often limited. This study explored the activity of different metal nanoparticles against several respiratory pathogens including MDROs.MethodsClinical isolates of carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Klebsiella pneumoniae (CRKP), Pseudomonas aeruginosa, Haemophilus influenzae, methicillin-resistant Staphylococcus aureus (MRSA), and Streptococcus pneumoniae were tested for in vitro susceptibilities to various antibiotics and nanoparticles. Minimum inhibitory concentrations (MICs) of silver-nanoparticle (Ag-NP), selenium-nanoparticle (Se-NP), and three composites solutions ND50, NK99, and TPNT1 (contained 5 ppm Ag-NP, 60 ppm ZnO-nanoparticle, and different concentrations of gold-nanoparticle or ClO₂) were determined by broth microdilution method.ResultsFifty isolates of each bacterial species listed above were tested. Ag-NP showed lower MICs to all species than Se-NP. The MIC₅₀s of Ag-NP for CRAB, CRKP, P. aeruginosa, and H. influenzae were <3.125 ppm, 25 ppm, <3.125 ppm, and <3.125 ppm, respectively, while those for S. pneumoniae and MRSA were >50 ppm and 50 ppm. Among CRAB, CRKP and P. aeruginosa, the MIC₅₀s of ND50, NK99, and TPNT1 for CRAB were the lowest (1/8 dilution, 1/8 dilution, and 1/8 dilution, respectively), and those for CRKP (>1/2 dilution, 1/2 dilution, and 1/2 dilution, respectively) were the highest. Both MRSA and S. pneumoniae showed high MIC₅₀s to ND50, NK99, and TPNT1.ConclusionsMetal nanoparticles had good in vitro activity against Gram-negative bacteria. They might be suitable to be prepared as environmental disinfectants or inhaled agents to inhibit the growth of MDR Gram-negative colonizers in the lower respiratory tracts of patients with chronic lung diseases.     

Nosocomial Outbreak of Carbapenem-Resistant Acinetobacter baumannii in Intensive Care Units and Successful Outbreak Control Program

Acinetobacter baumannii has been increasingly reported as a significant causative organism of various nosocomial infections. Here we describe an outbreak of carbapenem-resistant A. baumannii (CRAB) in the ICUs of a Korean university hospital, along with a successful outbreak control program. From October 2007 through July 2008, CRAB was isolated from 57 ICU patients. Nineteen patients were diagnosed as being truly infected with CRAB, four of whom were presumed to have died due to CRAB infection, producing a case-fatality rate of 21.1%. In surveillance of the environment and the healthcare workers (HCWs), CRAB was isolated from 24 (17.9%) of 135 environmental samples and seven (10.9%) of 65 HCWs. The pulsed field gel electrophoresis patterns showed that the isolates from patients, HCWs, and the environment were genetically related. Control of the outbreak was achieved by enforcing contact precautions, reducing environmental contamination through massive cleaning, and use of a closed-suctioning system. By August 2008 there were no new cases of CRAB in the ICUs. This study shows that the extensive spread of CRAB can happen through HCWs and the environmental contamination, and that proper strategies including strict contact precautions, massive environmental decontamination, and a closed-suctioning system can be effective for controlling CRAB outbreaks.     

Utility of Whole-Genome Sequencing in Characterizing Acinetobacter Epidemiology and Analyzing Hospital Outbreaks

Acinetobacter baumannii frequently causes nosocomial infections and outbreaks. Whole-genome sequencing (WGS) is a promising technique for strain typing and outbreak investigations. We compared the performance of conventional methods with WGS for strain typing clinical Acinetobacter isolates and analyzing a carbapenem-resistant A. baumannii (CRAB) outbreak. We performed two band-based typing techniques (pulsed-field gel electrophoresis and repetitive extragenic palindromic-PCR), multilocus sequence type (MLST) analysis, and WGS on 148 Acinetobacter calcoaceticus-A. baumannii complex bloodstream isolates collected from a single hospital from 2005 to 2012. Phylogenetic trees inferred from core-genome single nucleotide polymorphisms (SNPs) confirmed three Acinetobacter species within this collection. Four major A. baumannii clonal lineages (as defined by MLST) circulated during the study, three of which are globally distributed and one of which is novel. WGS indicated that a threshold of 2,500 core SNPs accurately distinguished A. baumannii isolates from different clonal lineages. The band-based techniques performed poorly in assigning isolates to clonal lineages and exhibited little agreement with sequence-based techniques. After applying WGS to a CRAB outbreak that occurred during the study, we identified a threshold of 2.5 core SNPs that distinguished nonoutbreak from outbreak strains. WGS was more discriminatory than the band-based techniques and was used to construct a more accurate transmission map that resolved many of the plausible transmission routes suggested by epidemiologic links. Our study demonstrates that WGS is superior to conventional techniques for A. baumannii strain typing and outbreak analysis. These findings support the incorporation of WGS into health care infection prevention efforts.     

Mortality and ventilator dependence in critically ill patients with ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii

BackgroundCarbapenem-resistant Acinetobacter baumannii (CRAB) is a key pathogen associated with ventilator-associated pneumonia (VAP). Research on treatment outcomes, especially ventilator dependence, in patients with VAP caused by CRAB remains limited.MethodsThis retrospective multicenter study included ICU-admitted patients with VAP caused by CRAB. The original cohort was included as the mortality evaluation cohort. The ventilator dependence evaluation cohort included cases that survived more than 21 days after VAP and without prolonged ventilation before VAP onset. The mortality rate, ventilator dependence rate, clinical factors associated with treatment outcomes, and treatment outcome differences with various VAP onset times were investigated.ResultsIn total, 401 patients with VAP caused by CRAB were analyzed. The 21-day all-cause mortality rate was 25.2%, and the 21-day ventilator dependence rate was 48.8%. Clinical factors associated with 21-day mortality included lower body mass index, higher sequential organ failure assessment score, vasopressors usage, CRAB persistence, and VAP onset time > seven days. Clinical factors associated with 21-day ventilator dependence included older age, vasopressors usage, and VAP onset time > seven days.ConclusionsICU-admitted patients with CRAB-related VAP had high mortality and ventilator dependence rates. Older age, vasopressor usage, and longer VAP onset time were independent factors associated with ventilator dependence.     

The interface between COVID-19 and bacterial healthcare-associated infections

BackgroundA wide range of bacterial infections occur in coronavirus disease 2019 (COVID-19) patients, particularly in those with severe coronaviral disease. Some of these are community-acquired co-infections.ObjectiveTo review recent data that indicate the occurrence of hospital-onset bacterial infections, including with antibiotic-resistant isolates, in COVID-19 patients.SourcesUsing PubMed, the literature was searched using terms including: ‘COVID-19’; ‘SARS-CoV-2’; ‘bacterial infection’; ‘healthcare-associated infection’; ‘antibiotic resistance’; ‘antimicrobial resistance’; ‘multi-drug resistance’; ‘Streptococcus’; ‘Staphylococcus’; ‘Pseudomonas’; ‘Escherichia’; ‘Klebsiella’; ‘Enterococcus’; ‘Acinetobacter’; ‘Haemophilus’; ‘MRSA’; ‘VRE’; ‘ESBL’; ‘NDM-CRE’; ‘CR-Ab’; ‘VRSA’; ‘MDR’.ContentThere is a growing number of reports of bacterial infections acquired by patients with severe COVID-19 after hospital admission. Antibiotic-resistant pathogens found to cause healthcare-associated infections (HAIs) in COVID-19 patients include methicillin-resistant Staphylococcus aureus, New Delhi metallo-β-lactamase-producing carbapenem-resistant Enterobacterales, carbapenem-resistant Acinetobacter baumannii, extended-spectrum β-lactamase Klebsiella pneumoniae and vancomycin-resistant enterococci. COVID-19 has impacted bacterial HAIs in a number of ways with an increase in the incidence of New Delhi metallo-β-lactamase-producing carbapenem-resistant Enterobacterales and carbapenem-resistant A. baumannii reported at some hospital sites compared with before the pandemic. Recommended guidelines for antimicrobial stewardship in COVID-19 patient treatment are discussed regarding minimization of empiric broad-spectrum antibiotic use. Other studies have reported a decrease in methicillin-resistant S. aureus and vancomycin-resistant enterococci cases, which has been attributed to enhanced infection prevention and control practices introduced to minimize intra-hospital spread of COVID-19.ImplicationsPoorer outcomes have been observed in hospitalized COVID-19 patients with an antibiotic-resistant infection. Although heightened IPC measures have been accompanied by a reduction in some HAIs at specific sites, in other situations, COVID-19 has been associated with an increase in bacterial HAI incidence. Further research is needed to define the cost–benefit relationship of maintaining COVID-19-related infection prevention and control protocols beyond the pandemic to reduce the burden of HAIs. In addition, the longer-term impact of high usage of certain broad-spectrum antibiotics during the COVID-19 pandemic requires evaluation.     

In vitro and In vivo Fitness of Clinical Isolates of Carbapenem-Resistant and -Susceptible Acinetobacter baumannii

Context: Acinetobacter baumannii is one among the leading nosocomial pathogens in the healthcare settings worldwide. Limited data on relative fitness and virulence of carbapenem-resistant A. baumannii (CRAB) are known. New methods are required to curb the rapidly rising antimicrobial resistance of this bug. Aims: We aimed to study the comparative in vitro and in vivo fitness of clinical isolates of CRAB and carbapenem-susceptible A. baumannii (CSAB). Settings and Design: A total of nine A. baumannii isolates were included in this study. CSAB ATCC-19606 was taken as a reference control strain. Subjects and Methods: Matrix-assisted laser desorption ionisation–time of flight mass spectrometry and gyrB and bla_OXA-51 PCR were used for species identification. Antimicrobial susceptibility was performed using Kirby-Bauer disk-diffusion method. Minimum inhibitory concentration for carbapenems (imipenem, meropenem and doripenem) was determined using agar dilution method. End point analysis, competitive index (CI), growth kinetics and generation time were determined for CRAB and CSAB isolates. In vivo fitness of CRAB and CSAB was determined using Caenorhabditis elegans host model. Multilocus sequence typing was performed to see the genetic relatedness of the isolates under study. Results: End point analysis, in vitro CI and growth kinetics experiments showed better fitness of clinical isolates of CRAB over CSAB ones. In vivo ‘nematode fertility assay’ using C. elegans also supported the in vitro results. Conclusions: To the best of our knowledge, this is the first study of its kind from India showing difference in fitness of clinical isolates of CRAB and CSAB.     

Carbapenem resistance and mortality in patients with Acinetobacter baumannii infection: systematic review and meta-analysis

Acinetobacter baumannii has emerged as a major cause of healthcare-associated infections. Controversy exists as to whether antimicrobial resistance increases the risk of mortality. We conducted a systematic review and meta-analysis to examine this association. We searched MEDLINE and EMBASE databases up to May 2013 to identify studies comparing mortality in patients with carbapenem-resistant A. baumannii (CRAB) vs. carbapenem-susceptible A. baumannii (CSAB). A random-effects model was used to pool Odds Ratios (OR). Heterogeneity was examined using I². We included 16 observational studies. There were 850 reported deaths (33%) among the 2546 patients. Patients with CRAB had a significantly higher risk of mortality than patients with CSAB in the pooled analysis of crude effect estimates (crude OR = 2.22; 95% CI = 1.66, 2.98), although substantial heterogeneity was evident (heterogeneity I² = 55%). The association remained significant in the pooled adjusted OR of 10 studies. Studies reported that patients with CRAB compared to patients with CSAB were more likely to have severe underlying illness and also to receive inappropriate empirical antimicrobial treatment, which increases the risk of mortality. Our study suggests that carbapenem resistance may increase the risk of mortality in patients with A. baumannii infection. However, cautious interpretation is required because of the residual confounding factors and inadequate sample size in most studies.     

Antibiotic treatment of infections caused by carbapenem-resistant Gram-negative bacilli: an international ESCMID cross-sectional survey among infectious diseases specialists practicing in large hospitals

ObjectivesTo explore contemporary antibiotic management of infections caused by carbapenem-resistant Gram-negative bacteria in hospitals.MethodsCross-sectional, internet-based questionnaire survey. We contacted representatives of all hospitals with more than 800 acute-care hospital beds in France, Greece, Israel, Italy, Kosovo, Slovenia, Spain and selected hospitals in the USA. We asked respondents to describe the most common actual practice at their hospital regarding management of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa through close-ended questions.ResultsBetween January and June 2017, 115 of 141 eligible hospitals participated (overall response rate 81.6%, country-specific rates 66.7%–100%). Most were tertiary-care (99/114, 86.8%), university-affiliated (110/115, 89.1%) hospitals and most representatives were infectious disease specialists (99/115, 86.1%). Combination therapy was prescribed in 114/115 (99.1%) hospitals at least occasionally. Respondents were more likely to consider combination therapy when treating bacteraemia, pneumonia and central nervous system infections and for Enterobacteriaceae, P. aeruginosa and A. baumannii similarly. Combination of a polymyxin with a carbapenem was used in most cases, whereas combinations of a polymyxin with tigecycline, an aminoglycoside, fosfomycin or rifampicin were also common. Monotherapy was used for treatment of complicated urinary tract infections, usually with an aminoglycoside or a polymyxin. The intended goal of combination therapy was to improve the effectiveness of the treatment and to prevent development of resistance. In general, respondents shared the misconception that combination therapy is supported by strong scientific evidence.ConclusionsCombination therapy was the preferred treatment strategy for infections caused by carbapenem-resistant Gram-negative bacteria among hospital representatives, even though high-quality evidence for carbapenem-based combination therapy is lacking.     

ESCMID-EUCIC clinical guidelines on decolonization of multidrug-resistant Gram-negative bacteria carriers

ScopeThe aim of these guidelines is to provide recommendations for decolonizing regimens targeting multidrug-resistant Gram-negative bacteria (MDR-GNB) carriers in all settings.MethodsThese evidence-based guidelines were produced after a systematic review of published studies on decolonization interventions targeting the following MDR-GNB: third-generation cephalosporin-resistant Enterobacteriaceae (3GCephRE), carbapenem-resistant Enterobacteriaceae (CRE), aminoglycoside-resistant Enterobacteriaceae (AGRE), fluoroquinolone-resistant Enterobacteriaceae (FQRE), extremely drug-resistant Pseudomonas aeruginosa (XDRPA), carbapenem-resistant Acinetobacter baumannii (CRAB), cotrimoxazole-resistant Stenotrophomonas maltophilia (CRSM), colistin-resistant Gram-negative organisms (CoRGNB), and pan-drug-resistant Gram-negative organisms (PDRGNB). The recommendations are grouped by MDR-GNB species. Faecal microbiota transplantation has been discussed separately. Four types of outcomes were evaluated for each target MDR-GNB:(a) microbiological outcomes (carriage and eradication rates) at treatment end and at specific post-treatment time-points; (b) clinical outcomes (attributable and all-cause mortality and infection incidence) at the same time-points and length of hospital stay; (c) epidemiological outcomes (acquisition incidence, transmission and outbreaks); and (d) adverse events of decolonization (including resistance development). The level of evidence for and strength of each recommendation were defined according to the GRADE approach. Consensus of a multidisciplinary expert panel was reached through a nominal-group technique for the final list of recommendations.RecommendationsThe panel does not recommend routine decolonization of 3GCephRE and CRE carriers. Evidence is currently insufficient to provide recommendations for or against any intervention in patients colonized with AGRE, CoRGNB, CRAB, CRSM, FQRE, PDRGNB and XDRPA. On the basis of the limited evidence of increased risk of CRE infections in immunocompromised carriers, the panel suggests designing high-quality prospective clinical studies to assess the risk of CRE infections in immunocompromised patients. These trials should include monitoring of development of resistance to decolonizing agents during treatment using stool cultures and antimicrobial susceptibility results according to the EUCAST clinical breakpoints.     

Antibiotic strategies and clinical outcomes in critically ill patients with pneumonia caused by carbapenem-resistant Acinetobacter baumannii

ObjectivesThis study aimed to investigate antibiotic prescribing patterns and effectiveness of different anti-carbapenem-resistant Acinetobacter baumannii (CRAB) strategies for CRAB pneumonia.MethodsWe conducted a multicentre, retrospective study in three hospitals. During 2010–2015, adult ICU patients with CRAB pneumonia treated with at least one antimicrobial agent covering the CRAB isolate in vitro for more than 2 days were included. We used multivariate logistic regression to analyse the associations of anti-CRAB strategies with ICU mortality and other clinical outcomes.ResultsAmong 238 patients with CRAB pneumonia, tigecycline monotherapy (84, 35.3%) was the most common antibiotic strategy, followed by tigecycline with colistin (43, 18.1%), colistin monotherapy (34, 14.3%), colistin combination without tigecycline (33, 13.9%), tigecycline combination without colistin (32, 13.4%), and sulbactam-based therapy without tigecycline and colistin (12, 5.0%). In multivariate analysis, tigecycline-based therapy was associated with higher ICU mortality than non-tigecycline therapy (adjusted OR 2.30, 95% CI 1.19–4.46). There was no difference between colistin-based therapy and non-colistin therapy. Compared with tigecycline monotherapy, colistin monotherapy was associated with lower ICU mortality (aOR 0.30, 95% CI 0.10–0.88). Treatment failure analyses showed similar trends. Tigecycline-based therapy was associated with higher treatment failure rate than non-tigecycline therapy (aOR 2.51, 95% CI 1.39–4.54), whereas colistin-based therapy was associated with lower treatment failure rate than non-colistin-based therapy (aOR 0.48, 95% CI 0.27–0.86).ConclusionsTigecycline was commonly prescribed for CRAB pneumonia. However, tigecycline-based therapy was associated with higher ICU mortality and treatment failure. Our study suggests that colistin monotherapy may be a better antibiotic strategy for CRAB pneumonia.     

Advances in the therapy of bacterial bloodstream infections

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

Role of early foldscopy (microscopy) of endotracheal tube aspirates in deciding restricted empirical therapy in ventilated patients

PurposePrevention of healthcare-associated infections (HAI) like ventilator associated pneumonia (VAP) is particularly challenging especially in resource limited settings. Complex microbial interactions between patients and health care workers (HCWs) further complicate the situation, requiring a holistic approach for successful management. To bridge the gap between laboratory and intensive care unit (ICU) this study was conducted to find the role of hand-held microscope ‘Foldscope’ in restricting empirical therapy in intubated patients.MethodsA total of 75 endotracheal aspirates (ETA) were collected from intubated patients in the ICU with (group 1) and without (group 2) VAP. For group 2, those with less than 48 ?h ventilation and with endotracheal tube (ETT) in situ were considered. Presence of biomass was detected through foldscope and ETA samples were processed for quantitative gram staining (QGS), semi-quantitative and quantitative culture. Phenotypic and genotypic characterization of Acinetobacter baumannii, the commonest isolate, was done and findings were statistically analysed.ResultsBiomass was present as seen through a foldscope in 45 cases (90%) in group 1 and 17 cases (68%) in group 2. In both the groups, A. baumannii was the most common isolate. Biomass production, significant QGS and culture was significantly more in group 1 (p ?< ?0.05). However, carbapenem resistant A. baumannii (CRAB) was comparably present in both the groups thus showing limited role of empirical carbapenem therapy.ConclusionsEarly assessment of biomass in mechanically ventilated patients could provide guidance for empirical antibiotic therapy. Foldscope proved to be an excellent tool for restricting empirical therapy and driving antimicrobial stewardship in low resource settings.     

Using machine learning to optimize antibiotic combinations: dosing strategies for meropenem and polymyxin B against carbapenem-resistant Acinetobacter baumannii

ObjectivesIncreased rates of carbapenem-resistant strains of Acinetobacter baumannii have forced clinicians to rely upon last-line agents, such as the polymyxins, or empirical, unoptimized combination therapy. Therefore, the objectives of this study were: (a) to evaluate the in vitro pharmacodynamics of meropenem and polymyxin B (PMB) combinations against A. baumannii; (b) to utilize a mechanism-based mathematical model to quantify bacterial killing; and (c) to develop a genetic algorithm (GA) to define optimal dosing strategies for meropenem and PMB.MethodsA. baumannii (N16870; MIC_meropenem = 16 mg/L, MIC_PMB = 0.5 mg/L) was studied in the hollow-fibre infection model (initial inoculum 10⁸ cfu/mL) over 14 days against meropenem and PMB combinations. A mechanism-based model of the data and population pharmacokinetics of each drug were used to develop a GA to define the optimal regimen parameters.ResultsMonotherapies resulted in regrowth to ~10¹⁰ cfu/mL by 24 h, while combination regimens employing high-intensity PMB exposure achieved complete bacterial eradication (0 cfu/mL) by 336 h. The mechanism-based model demonstrated an SC₅₀ (PMB concentration for 50% of maximum synergy on meropenem killing) of 0.0927 mg/L for PMB-susceptible subpopulations versus 3.40 mg/L for PMB-resistant subpopulations. The GA had a preference for meropenem regimens that improved the %T > MIC via longer infusion times and shorter dosing intervals. The GA predicted that treating 90% of simulated subjects harbouring a 10⁸ cfu/mL starting inoculum to a point of 10⁰ cfu/mL would require a regimen of meropenem 19.6 g/day 2 h prolonged infusion (2 hPI) q5h + PMB 5.17 mg/kg/day 2 hPI q6h (where the 0 h meropenem and PMB doses should be ‘loaded’ with 80.5% and 42.2% of the daily dose, respectively).ConclusionThis study provides a methodology leveraging in vitro experimental data, a mathematical pharmacodynamic model, and population pharmacokinetics provide a possible avenue to optimize treatment regimens beyond the use of the ‘traditional’ indices of antibiotic action.     

Epidemiological characterization and distribution of carbapenem-resistant Acinetobacter baumannii clinical isolates in Italy

This study was aimed at tracing the molecular characteristics of carbapenem-resistant Acinetobacter baumannii (CRAB) clinical isolates in Italy with both pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Two hundred and two CRAB isolates were collected during 2004–2009, in two different surveillance periods, from 22 Italian hospitals that were representative for both distribution and infection. PFGE was performed, and the MLST scheme used was based on the gene sequence as published on the MLST Pasteur website http://www.pasteur.fr/mlst. Representatives of the major European clones I (RUH 875) and II (RUH 134) were used as controls. The two groups of isolates were characterized for their carbapenem resistance genes: 154 of 202 carried bla_OXA-58 alone, 21 of 202 also carried bla_OXA-23, and 27 of 202 carried bla_OXA-23 alone. No isolates were positive for bla_OXA-24. Genotype analysis of all isolates identified four distinct patterns by PFGE, which correlated with four distinct sequence types (STs) by MLST. The distribution of these four clusters in Italy confirmed the propensity of A. baumannii for nosocomial cross-transmission in a vast geographical area. We observed that clones A and B had similarities with European clone II and I respectively. By MLST, clone A was ST2, like European clone II, and clone B was ST1, like European clone I. PFGE and MLST showed the same discriminatory power and reproducibility. In addition, the two methods were concordant in defining CRAB Italian clones and in correlating them with the two pan-European clones.     

The combined use of tigecycline with high-dose colistin might not be associated with higher survival in critically ill patients with bacteraemia due to carbapenem-resistant Acinetobacter baumannii

ObjectiveTo assess the association of survival and treatment with colistin and tigecycline in critically ill patients with carbapenem-resistant Acinetobacter baumannii bacteraemia.MethodsAn observational cohort study was carried out. Targeted therapy consisted of monotherapy with colistin (9 million UI/day) or combined therapy with colistin and tigecycline (100 g/day). The primary outcome was 30-day crude mortality. The association between combined targeted therapy and mortality was controlled for empirical therapy with colistin, propensity score of combined therapy and other potential confounding variables in a multivariate Cox regression analysis.ResultsA total of 118 cases were analysed. Seventy-six patients (64%) received monotherapy and 42 patients (36%) received combined therapy. The source of bacteraemia was primary in 18% (21/118) of the patients, ventilator-associated pneumonia in 64% (76/118) and other sources in 14% (16/118). The 30-day crude mortality rate was 62% (42/76) for monotherapy and 57% (24/42) for combined therapy. The variables associated with 30-day crude mortality were: Charlson index (hazard ratio (HR) 1.16, 95% CI 1.02–1.32; p 0.028), empirical therapy with colistin (HR 2.25, 95% CI 1.33–3.80; p 0.003) and renal dysfunction before treatment (HR 1.91, 95% CI 1.01–3.61; p 0.045). Combined targeted therapy was not associated with lower adjusted 30-day crude mortality (adjusted HR 1.29, 95% CI 0.64–2.58; p 0.494).ConclusionsCombined targeted therapy with high-dose colistin and standard dose tigecycline was not associated with lower crude mortality of bacteraemia due to carbapenem-resistant A. baumannii in critically ill patients.Trial registrationRegistered in ClinicalTrials.gov. Identifier: NCT02573064.     

<Emphasis Type="Italic">Acinetobacter baumannii</Emphasis> bacteraemia in patients with haematological malignancy: a multicentre retrospective study from the Infection Working Party of Jiangsu Society of Hematology

Acinetobacter baumannii (Ab) bacteraemia in patients with haematological malignancies is fatal but rarely reported. We explored the clinical characteristics, drug resistances and prognostic factors in these patients. This multicentre, retrospective study was conducted at the department of haematology wards of 18 tertiary hospitals in China from January 2014 to June 2015. The total clinical isolates from every source were collected from patients with haematological malignancy. Haematological malignancy patients diagnosed with Ab bacteraemia were analysed. During the study period, 40 patients with Ab bacteraemia were identified, accounting for 2.9% (40/1358) of bacteraemia cases, of which 25 (62.5%) had acute leukaemia (AL) and 27 (67.5%) had neutropaenia. Compared with non-neutropaenic patients, neutropaenic patients showed higher Acute Physiology and Chronic Health Evaluation (APACHE) scores and 30-day mortality rates (p?<?0.05). The in vitro antibiotic susceptibility of Ab to colistin was highest, at 100%, followed by that of tigecycline (91.30%) and amikacin (75.86%). Compared with the patients who had carbapenem-susceptible Ab infections, patients infected with carbapenem-resistant Ab (CRAB) had significantly longer hospital stays and were more likely to have had exposure to carbapenem before bacteraemia (p?<?0.05). The 30-day mortality rate was 32.5%. CRAB, neutropaenia, higher APACHE score, Pitt bacteraemia score and inappropriate initial antimicrobial therapy were significantly associated with 30-day mortality. Multivariable analysis showed that APACHE score and CRAB were independent predictors of 30-day mortality. Haematologic patients with AL and febrile neutropaenia were at high risk of Ab bacteraemia. More attention should be paid to CRAB, which is an independent risk factor for mortality in haematological malignancy patients with Ab bacteraemia.