Acinetobacter baumannii is an important nosocomial pathogen that accounts for up to 20 percent of infections in intensive care units worldwide. Furthermore, A. baumannii strains have emerged that are resistant to all available antimicrobials. These facts highlight the dire need for new therapeutic strategies to combat this growing public health threat. Given the critical role for transition metals at the pathogen-host interface, interrogating the role for these metals in A. baumannii physiology and pathogenesis could elucidate novel therapeutic strategies. Toward this end, the role for calprotectin- (CP)-mediated chelation of manganese (Mn) and zinc (Zn) in defense against A. baumannii was investigated. These experiments revealed that CP inhibits A. baumannii growth in vitro through chelation of Mn and Zn. Consistent with these in vitro data, Imaging Mass Spectrometry revealed that CP accompanies neutrophil recruitment to the lung and accumulates at foci of infection in a murine model of A. baumannii pneumonia. CP contributes to host survival and control of bacterial replication in the lung and limits dissemination to secondary sites. Using CP as a probe identified an A. baumannii Zn acquisition system that contributes to Zn uptake, enabling this organism to resist CP-mediated metal chelation, which enhances pathogenesis. Moreover, evidence is provided that Zn uptake across the outer membrane is an energy-dependent process in A. baumannii. Finally, it is shown that Zn limitation reverses carbapenem resistance in multidrug resistant A. baumannii underscoring the clinical relevance of these findings. Taken together, these data establish Zn acquisition systems as viable therapeutic targets to combat multidrug resistant A. baumannii infections.
Infections by A. calcoaceticus-A. baumannii (ACB) complex isolates represent a serious threat for wounded and burn patients. Three international multidrug-resistant (MDR) clones (EU clone I-III) are responsible for a large proportion of nosocomial infections with A. baumannii but other emerging strains with high epidemic potential also occur.
For its remarkable ability to acquire antibiotic resistance and to survive in nosocomial environments, Acinetobacter baumannii has become a significant nosocomial infectious agent worldwide. Tigecycline is one of the few therapeutic options to treat infections caused by A. baumannii isolates. However, tigecycline resistance has been increasingly reported. Our aim was to assess the prevalence and characteristics of efflux-based tigecycline resistance in clinical isolates of A. baumannii collected from a hospital in China. A total of 74 A. baumannii isolates including 64 tigecycline non-susceptible A. baumannii (TNAB) and 10 tigecycline susceptible A. baumannii (TSAB) isolates were analyzed. The majority of them were detected to be positive for adeABC, adeRS, adeIJK and abeM, while the adeE gene was found in only one TSAB isolate. Compared with TSAB isolates, the mean expression level of adeB, adeJ, adeG and abeM in TNAB isolates were observed to increase by 29-, 3-, 0.7- and 1-fold, respectively. The efflux pump inhibitors (EPIs) PAβN and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) could partially reverse the resistance pattern of tigecycline. Moreover, tetX1 gene was detected in 12 (18.8%) TNAB isolates. To our knowledge, this is the first report that tetX1 gene was detected in the A. baumannii isolates. ST208 and ST191 which both clustered into clonal complex 92 (CC92) were the predominant sequence types (STs). This study showed that active efflux pump AdeABC appeared to play important roles in the tigecycline resistance of A. baumannii. The dissemination of TNAB isolates in our hospital is mainly attributable to the spread of CC92.
Acinetobacter baumannii is a common nosocomial pathogen and strain-typing method important in hospital outbreak investigations and epidemiologic surveillance. We describe a method for identifying strain-specific peptide markers based on LC-MS/MS profiling of digested peptides. This method classified a test set of A. baumannii isolates collected from a hospital outbreak with discriminatory performance exceeding that of MALDI-TOF mass spectrometry.
Pseudomonas aeruginosa is a pathogen that is prevalent in serious infections in compromised patients worldwide. A unique virulence factor of this bacterium is the redox-active molecule pyocyanin, which is a potential biomarker for the identification of P. aeruginosa infections. Here we report a direct, selective and rapid detection technique of pyocyanin.
Cefiderocol (formerly S-649266) is an investigational siderophore cephalosporin. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) was prepared according to the Clinical and Laboratory Standards Institute (CLSI) protocol and used to perform broth microdilution testing of cefiderocol against a 2014-2015 collection of clinical isolates of gram-negative bacilli from North America (n=4,239) and Europe (n=4,966). The concentration of cefiderocol inhibiting 90% of isolates tested (MIC90) was: 0.5 (North America; n=3,007) and 1 μg/ml (Europe; n=3,080) for all isolates of Enterobacteriaceae; 1 (North America; n=30) and 4 μg/ml (Europe; n=139) for meropenem-non-susceptible (MIC ≥2 μg/ml) isolates of Enterobacteriaceae; 0.5 μg/ml for both North American (n=765) and European (n=765) isolates of Pseudomonas aeruginosa; 0.5 (North America; n=151) and 1 μg/ml (Europe; n=202) for meropenem-non-susceptible (MIC ≥4 μg/ml) isolates of P. aeruginosa; 1 μg/ml for both North American (n=309) and European (n=839) isolates of all Acinetobacter baumannii as well as for both North American (n=173) and European (n=595) isolates of meropenem-non-susceptible A. baumannii; and 0.5 (North America; n=152) and 0.25 μg/ml (Europe; n=276) for isolates of Stenotrophomonas maltophilia MICs to cefiderocol were ≤4 μg/ml for 99.9% (6,078/6,087) of all Enterobacteriaceae, 97.0% (164/169) of meropenem-non-susceptible Enterobacteriaceae, 99.9% (1,529/1,530) of all P. aeruginosa, 100% (353/353) of meropenem-non-susceptible P. aeruginosa, 97.6% (1,120/1,148) of all A. baumannii, 96.9% (744/768) of meropenem-non-susceptible A. baumannii, 100% of isolates of S. maltophilia (428/428) and 93.8% of Burkholderia cepecia (11/12). We conclude that cefiderocol demonstrated potent in vitro activity against a recent collection of clinical isolates of commonly encountered gram-negative bacilli, including carbapenem non-susceptible isolates.
- Journal of the Pediatric Infectious Diseases Society
- Published about 2 years ago
Acinetobacter baumannii is a common cause of healthcare-associated infections. Carbapenem-resistant (CR) A baumannii is a significant threat globally. We used a large reference laboratory database to study the epidemiology of A baumannii in children in the United States.
In this study, the degradation of tetradecyltrimethylammonium bromide (TTAB) by freely suspended and alginate-entrapped cells from the bacteria Pseudomonas putida (P. putida) A ATCC 12633 was investigated in batch cultures. The optimal conditions to prepare beads for achieving a higher TTAB degradation rate were investigated by changing the concentration of sodium alginate, pH, temperature, agitation rate and initial concentration of TTAB. The results show that the optimal embedding conditions of calcium alginate beads are 4 % w/v of sodium alginate content and 2 × 10(8) cfu ml(-1) of P. putida A ATCC 12633 cells that had been previously grown in rich medium. The optimal degradation process was carried out in pH 7.4 buffered medium at 30 °C on a rotary shaker at 100 rpm. After 48 h of incubation, the free cells degraded 26 mg l(-1) of TTAB from an initial concentration of 50 mg l(-1) TTAB. When the initial TTAB concentration was increased to 100 mg l(-1), the free cells lost their degrading activity and were no longer viable. In contrast, when the cells were immobilized on alginate, they degraded 75 % of the TTAB after 24 h of incubation from an initial concentration of 330 mg l(-1) of TTAB. The immobilized cells can be stored at 4 °C for 25 days without loss of viability and can be reused without losing degrading capacity for three cycles.
: Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a serious threat among critically ill neonates.
Ceftolozane is a new cephalosporin with potent activity against Pseudomonas aeruginosa and Enterobacteriaceae. The neutropenic murine thigh-infection was used to determine which pharmacokinetic/pharmacodynamic index and magnitude drives efficacy of ceftolozane with gram-negative bacilli, compare the rate of in-vivo killing of ceftolozane with ceftazidime against P. aeruginosa, and determine the impact of different ratios of ceftolozane plus tazobactam on Enterobacteriaceae containing extended-spectrum-β-lactamases (ESBLs). Neutropenic mice had 10(6.2-7.1) cfu/thigh when treated with ceftolozane for 24 h with  varying doses (3.12 to 1600 mg/kg) and dosage intervals (3, 6, 12 and 24 h) against 2 Enterobacteriaceae,  0.39-800 mg/kg every 6 h for 4 Enterobacteriaceae and 4 P. aeruginosa, and  400 or 800 mg/kg with 2:1. 4:1, and 8:1 ratios of tazobactam against 5 Enterobacteriaceae with ESBLs. Pharmacokinetics of ceftolozane at 25, 100, and 400 mg/kg was linear with peak/dose values of 1.0-1.4 and half-lives of 12-14 min. T>MIC was the primary index driving efficacy. For stasis (1 log kill), T>MIC was 26.3% ± 2.1 (31.6% ± 1.6) for wild-type Enterobacteriaceae, 31.1% ± 4.9 (34.8% ±4.4) for Enterobacteriaceae with ESBLs, and 24.0% ± 3.3 (31.5% ± 3.9) for P. aeruginosa. At 200 mg/kg every 3 h, the rate of in-vivo killing of P. aeruginosa was faster with ceftolozane than with ceftazidime (-0.34 to -0.41 versus -0.21 to -0.24 log(10) cfu/thigh/h). The 2:1 ratio of ceftolozane with tazobactam was the most potent combination studied. T>MIC required for ceftolozane is less than with other cephalosporins and may be due to more rapid killing.