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1.  Clinical Outcomes of Tigecycline in the Treatment of Multidrug-Resistant Acinetobacter baumannii Infection 
Yonsei Medical Journal  2012;53(5):974-984.
Purpose
Acinetobacter baumannii (A. baumannii) has emerged as a major cause of nosocomial pneumonia and sepsis in seriously ill patients. Multidrug-resistant A. baumannii (MDRAB) is increasing in frequency, and the management of it's infections is consequently difficult. Therefore, tigecycline is considered to be the drug of choice for MDRAB treatment. The aim of our study was to evaluate the microbiological eradication and clinical effectiveness of tigecycline against MDRAB in seriously ill patients, including patients with ventilator-associated pneumonia (VAP).
Materials and Methods
We conducted a retrospective study including patients with A. baumannii infections who were treated with tigecycline between April 1, 2009 and March 31, 2010. We treated 27 patients with tigecycline for MDRAB infections.
Results
The mean age of patients was 66.2 years, and 20 (74.1%) patients were male. The median length of stay at hospital was 74.6 days. MDRAB was eradicated from the site of infection in 23 cases (85.2%), however, only 17 cases (63.0%) showed positive clinical responses. Overall, an in-hospital mortality rate of 51.9% was observed, and 4 cases of death were attributable to sepsis. The combination therapy showed better clinical and microbial success rates than the monotherapy without significant difference.
Conclusion
We observed the relatively low clinical success rate although the microbial eradication rate was high, probably due to superinfections in VAP and bacteremia. We suggest that clinicians should limit tigecycline monotherapy for MDRAB infection in critically ill patients, until large controlled clinical trials should be conducted.
doi:10.3349/ymj.2012.53.5.974
PMCID: PMC3423844  PMID: 22869481
Acinetobacter baumannii; bacteremia; multidrug resistance; tigecycline; ventilator-associated pneumonia
2.  Multidrug Resistant Acinetobacter baumannii: Risk Factors for Appearance of Imipenem Resistant Strains on Patients Formerly with Susceptible Strains 
PLoS ONE  2010;5(4):e9947.
Background
Multidrug resistant Acinetobacter baumannii (MDRAB) is an important nosocomial pathogen usually susceptible to carbapenems; however, growing number of imipenem resistant MDRAB (IR-MDRAB) poses further clinical challenge. The study was designed to identify the risk factors for appearance of IR-MDRAB on patients formerly with imipenem susceptible MDRAB (IS-MDRAB) and the impact on clinical outcomes.
Methodology/Principal Findings
A retrospective case control study was carried out for 209 consecutive episodes of IS-MDRAB infection or colonization from August 2001 to March 2005. Forty-nine (23.4%) episodes with succeeding clinical isolates of IR-MDRAB were defined as the cases and 160 (76.6%) with all subsequent clinical isolates of IS-MDRAB were defined as the controls. Quantified antimicrobial selective pressure, “time at risk”, severity of illness, comorbidity, and demographic data were incorporated for multivariate analysis, which revealed imipenem or meropenem as the only significant independent risk factor for the appearance of IR-MDRAB (adjusted OR, 1.18; 95% CI, 1.09 to 1.27). With selected cases and controls matched to exclude exogenous source of IR-MDRAB, multivariate analysis still identified carbapenem as the only independent risk factor (adjusted OR, 1.48; 95% CI, 1.14 to 1.92). Case patients had a higher crude mortality rate compared to control patients (57.1% vs. 31.3%, p = 0.001), and the mortality of case patients was associated with shorter duration of “time at risk”, i.e., faster appearance of IR-MDRAB (adjusted OR, 0.9; 95% CI, 0.83 to 0.98).
Conclusions/Significance
Judicious use of carbapenem with deployment of antibiotics stewardship measures is critical for reducing IR-MDRAB and the associated unfavorable outcome.
doi:10.1371/journal.pone.0009947
PMCID: PMC2846922  PMID: 20369056
3.  Risk factors and antibiotic resistance of pneumonia caused by multidrug resistant Acinetobacter baumannii in pediatric intensive care unit 
BACKGROUND:
With beta-lactam drugs and immunosuppressants widely used, the infection caused by Acinetobacter baumannii (Ab) has become more and more serious with multidrug resistant Acinetobacter baumannii (MDRAb) emerging and worsening rapidly. Compared with other patients, the incidence and multidrug resistance of MDRAb are higher in children in pediatric intensive care unit (PICU) because of immune deficiency, severe basic diseases, prolonged hospitalization and invasive operations. Hence it is significant to study the epidemiology and changes of antibacterial susceptibility in order to reduce the incidence of MDRAb in children.
METHODS:
A total 115 patients with MDRAb pneumonia and 45 patients with negative MDRAb (NMDRAb) pneumonia who had been treated from January 2009 to August 2011 were studied retrospectively at the PICU of Wuhan Children’s Hospital. Clinical data were analyzed with univariate and multivariate Logistic regression.
RESULTS:
In 176 clinical strains of Acinetobacter baumannii isolated, there were 128 strains of MDRAb, accounting for 72.73%. Drug susceptibility tests showed that the resistance rates of β-lactam antibiotics were more than 70% except for cefoperazone sulbactam. The rates to carbapenems were higher than 90%. They were significantly higher than those of NMDRAb. Amikacin, levofloxacin, ciprofloxacin and minocycline had the lowest drug-resistance rates (<20%). Multivariate Logistic regression revealed that ICU stay, the time of mechanical ventilation, anemia, hypoproteinemia and the use of carbapenems were independent risk factors for MDRAb pneumonia.
CONCLUSIONS:
MDRAb is an important opportunistic pathogen to pneumonia in PICU, and its drug-resistance is severe. It increases significantly the mortality of patients. It is important to take the effective prevention measures for controlling it.
doi:10.5847/wjem.j.issn.1920-8642.2012.03.008
PMCID: PMC4129778  PMID: 25215064
Pediatric; Intensive Care Unit; Multidrug resistance; Acinetobacter baumannii; Pneumonia; Risk factor; Retrospective study
4.  Tracing the emergence of multidrug-resistant Acinetobacter baumannii in a Taiwanese hospital by evaluating the presence of integron gene intI1 
Background
In Changhua County, Taiwan, the number of clinical Acinetobacter baumannii isolates has risen since 2002, and multidrug-resistant Acinetobacter baumannii (MDRAB) has spread rapidly throughout Taiwan. In this study, to reveal the mechanism involved with the rapid dissemination of MDRAB emergence, the utility of the class 1 integron, intI1 integrase gene, as an MDRAB-associated biomarker was examined. A cross-sectional, clinical epidemiological study was performed at Changhua Christian Hospital between January 1st, 2001 and December 31st, 2004. Besides the existence of intI1 gene was examined, the pulse-field gel electrophoresis (PFGE) was also performed to determine the epidemiological characteristics of the isolates.
Findings
The overall hospital infection rate was 5–6%, while the infection rate of the intensive care unit (ICU) fluctuated. No positive correlation was observed between MDRAB isolates and the presence of intI1 (r = 0.168, P = 0.254). Additionally, no positive correlation was observed between the infection rate in the ICU and the presence of intI1 (r = -0.107, P = 0.468) or between the hospital infection rate and the presence of intI1 (r = -0.189, P = 0.199). However, two predominant clones among the MDRAB isolates were identified by PFGE.
Conclusions
Although the presence of the intI1 gene does not seem suitable for tracing MDRAB emergence in Changhua County, two predominant clones were identified by PFGE, and subsequent studies to identify whether these clones were responsible for original nosocomial infection are needed.
doi:10.1186/1477-5751-13-15
PMCID: PMC4155391  PMID: 25123361
Acinetobacter baumannii; IntI1 gene; Class 1 integron
5.  Effectiveness of tigecycline-based versus colistin- based therapy for treatment of pneumonia caused by multidrug-resistant Acinetobacter baumannii in a critical setting: a matched cohort analysis 
BMC Infectious Diseases  2014;14:102.
Background
Colistin and tigecycline have both been shown good in vitro activity among multi-drug resistant Acinetobacter baumannii (MDRAB). A comparative study of colistin versus tigecycline for MDRAB pneumonia is lacking.
Methods
The study enrolled adults with MDRAB pneumonia admitted to intensive care units at a referral medical center during 2009–2010. Since there were no standardized minimum inhibitory concentration (MIC) interpretation criteria of tigecycline against A. baumannii, MIC of tigecycline was not routinely tested at our hospital. During the study periods, MIC of colistin was not routinely tested also. We consider both colistin and tigecycline as definite treatments of MDRAB pneumonia. Patients who received tigecycline were selected as potential controls for those who had received colistin. We performed a propensity score analysis, by considering the criteria of age, gender, underlying diseases, and disease severity, in order to match and equalize potential prognostic factors and severity in the two groups.
Results
A total of 294 adults with MDRAB pneumonia were enrolled, including 119 who received colistin and 175 who received tigecycline. We matched 84 adults who received colistin with an equal number of controls who received tigecycline. The two well matched cohorts share similar characteristics: the propensity scores are colistin: 0.37 vs. tigecycline: 0.37, (P = .97); baseline creatinine (1.70 vs. 1.81, P = .50), and the APACHE II score (21.6 vs. 22.0, P = .99). The tigecycline group has an excess mortality of 16.7% (60.7% vs. 44%, 95% confidence interval 0.9% – 32.4%, P = .04). The excess mortality of tigecycline is significant only among those with MIC >2 μg/mL (10/12 vs. 37/84, P = .01), but not for those with MIC ≦ 2 μg/mL (4/10 vs. 37/84, P = .81).
Conclusions
Our data disfavors the use of tigecycline-based treatment in treating MDRAB pneumonia when tigecycline and colistin susceptibilities are unknown, since choosing tigecycline-based treatment might result in higher mortality. The excess mortality of tigecycline-based group may be related to higher MIC of tigecycline (> 2 μg/mL). Choosing tigecycline empirically for treating MDRAB pneumonia in the critical setting should be cautious.
doi:10.1186/1471-2334-14-102
PMCID: PMC3936940  PMID: 24564226
Acinetobacter baumannii; Pneumonia; Colistin; Tigecycline; Mortality; Nephrotoxicity
6.  Potential of bacteriophage ΦAB2 as an environmental biocontrol agent for the control of multidrug-resistant Acinetobacter baumannii 
BMC Microbiology  2013;13:154.
Background
Multidrug-resistant Acinetobacter baumannii (MDRAB) is associated with nosocomial infections worldwide. To date, the use of a phage to prevent infections caused by MDRAB has not been demonstrated.
Results
The MDRAB-specific phage ϕAB2 was stable at 4°C and pH 7 in 0.5% chloroform solution, and showed a slight decrease in plaque-forming units (PFU)/ml of 0.3–0.9 log after 330 days of storage. The addition of ϕAB2 at a concentration of at least 105 PFU/ml to an A. baumannii M3237 suspension killed >99.9% of A. baumannii M3237 after 5 min, regardless of A. baumannii M3237 concentration (104, 105, or 106 colony-forming units (CFU)/ml). The addition of ϕAB2 at a concentration of 108 PFU/slide (>107 PFU/cm2) to glass slides containing A. baumannii M3237 at 104, 105, or 106 CFU/slide, significantly reduced bacterial numbers by 93%, 97%, and 99%, respectively. Thus, this concentration is recommended for decontamination of glass surfaces. Moreover, infusion of ϕAB2 into 10% glycerol exhibited strong anti-MDRAB activity (99.9% reduction), even after 90 days of storage. Treatment of a 10% paraffin oil-based lotion with ϕAB2 significantly reduced (99%) A. baumannii M3237 after 1 day of storage. However, ϕAB2 had no activity in the lotion after 1 month of storage.
Conclusions
Phages may be useful for reducing MDRAB contamination in liquid suspensions or on hard surfaces. Phages may also be inoculated into a solution to produce an antiseptic hand wash. However, the phage concentration and incubation time (the duration of phage contact with bacteria) should be carefully considered to reduce the risk of MDRAB contamination.
doi:10.1186/1471-2180-13-154
PMCID: PMC3710471  PMID: 23834712
Bacteriophage; Biocontrol; MDRAB
7.  A randomized, controlled trial of enhanced cleaning to reduce contamination of healthcare worker gowns and gloves with multidrug-resistant bacteria 
Objective
To determine whether enhanced daily cleaning would reduce contamination of healthcare worker (HCW) gowns and gloves with methicillin-resistant Staphylococcus aureus (MRSA) or multidrug-resistant Acinetobacter baumannii (MDRAB).
Design
A cluster-randomized controlled trial.
Setting
Four intensive care units (ICUs) in an urban tertiary care hospital.
Participants
ICU rooms occupied by patients colonized with MRSA or MDRAB.
Intervention
Extra enhanced daily cleaning of ICU room surfaces frequently touched by HCWs.
Results
A total of 4,444 cultures were collected from 132 rooms over 10 months. Using fluorescent dot markers at 2,199 surfaces, we found that 26% of surfaces in control rooms were cleaned and 100% of surfaces in experimental rooms were cleaned (p < 0.001). The mean proportion of contaminated HCW gowns and gloves following routine care provision and before leaving the rooms of patients with MDRAB was 16% among control rooms and 12% among experimental rooms (RR: 0.77, 95% CI: 0.28 – 2.11, p = 0.230). For MRSA, the mean proportions were 22% and 19%, respectively (RR: 0.89, 95%: 0.5 – 1.53, p = 0.158).
Discussion
Intense enhanced daily cleaning of ICU rooms occupied by patients colonized with MRSA or MDRAB was associated with a nonsignificant reduction in contamination of HCW gowns and gloves after routine patient care activities. Further research is needed to determine whether intense environmental cleaning will lead to significant reductions and fewer infections.
doi:10.1086/670205
PMCID: PMC3759983  PMID: 23571365
8.  Azithromycin Attenuates Lung Inflammation in a Mouse Model of Ventilator-Associated Pneumonia by Multidrug-Resistant Acinetobacter baumannii 
Acinetobacter baumannii is one of the main pathogens that cause ventilator-associated pneumonia (VAP) and is associated with a high rate of mortality. Little is known about the efficacy of macrolides against A. baumannii. In order to confirm the efficacy of azithromycin (AZM) against VAP caused by multidrug-resistant A. baumannii (MDRAB), we used a mouse model that mimics VAP by placement of a plastic tube in the bronchus. AZM (10 and 100 mg/kg of body weight) was administered subcutaneously every 24 h beginning at 3 h after inoculation. Phosphate-buffered saline was administered as the control. Survival was evaluated over 7 days. At 48 h postinfection, mice were sacrificed and the numbers of viable bacteria in lungs and bronchoalveolar lavage fluid were compared. Histopathological analysis of lung specimens was also performed. The treatment groups displayed significantly longer survival than the control group (P < 0.05). AZM did not have an antimicrobial effect. Histopathological examination of lung specimens indicated that the progression of lung inflammation was prevented in the AZM-treated groups. Furthermore, total cell and neutrophil counts, as well as cytokine levels, in bronchoalveolar lavage fluid were significantly decreased (P < 0.05) in the AZM-treated groups. AZM may have a role for the treatment of VAP with MDRAB because of its anti-inflammatory effects.
doi:10.1128/AAC.00457-13
PMCID: PMC3719704  PMID: 23733468
9.  Identifying More Epidemic Clones during a Hospital Outbreak of Multidrug-Resistant Acinetobacter baumannii 
PLoS ONE  2012;7(9):e45758.
Infections caused by multidrug-resistant bacteria are a major concern in hospitals. Current infection-control practices legitimately focus on hygiene and appropriate use of antibiotics. However, little is known about the intrinsic abilities of some bacterial strains to cause outbreaks. They can be measured at a population level by the pathogen’s transmission rate, i.e. the rate at which the pathogen is transmitted from colonized hosts to susceptible hosts, or its reproduction number, counting the number of secondary cases per infected/colonized host. We collected data covering a 20-month surveillance period for carriage of multidrug-resistant Acinetobacter baumannii (MDRAB) in a surgery ward. All isolates were subjected to molecular fingerprinting, and a cluster analysis of profiles was performed to identify clonal groups. We then applied stochastic transmission models to infer transmission rates of MDRAB and each MDRAB clone. Molecular fingerprinting indicated that 3 clonal complexes spread in the ward. A first model, not accounting for different clones, quantified the level of in-ward cross-transmission, with an estimated transmission rate of 0.03/day (95% credible interval [0.012–0.049]) and a single-admission reproduction number of 0.61 [0.30–1.02]. The second model, accounting for different clones, suggested an enhanced transmissibility of clone 3 (transmission rate 0.047/day [0.018–0.091], with a single-admission reproduction number of 0.81 [0.30–1.56]). Clones 1 and 2 had comparable transmission rates (respectively, 0.016 [0.001–0.045], 0.014 [0.001–0.045]). The method used is broadly applicable to other nosocomial pathogens, as long as surveillance data and genotyping information are available. Building on these results, more epidemic clones could be identified, and could lead to follow-up studies dissecting the functional basis for variation in transmissibility of MDRAB lineages.
doi:10.1371/journal.pone.0045758
PMCID: PMC3459964  PMID: 23029226
10.  Antimicrobial resistance in Acinetobacter baumannii: From bench to bedside 
Acinetobacter baumannii (A. baumannii) is undoubtedly one of the most successful pathogens in the modern healthcare system. With invasive procedures, antibiotic use and immunocompromised hosts increasing in recent years, A. baumannii has become endemic in hospitals due to its versatile genetic machinery, which allows it to quickly evolve resistance factors, and to its remarkable ability to tolerate harsh environments. Infections and outbreaks caused by multidrug-resistant A. baumannii (MDRAB) are prevalent and have been reported worldwide over the past twenty or more years. To address this problem effectively, knowledge of species identification, typing methods, clinical manifestations, risk factors, and virulence factors is essential. The global epidemiology of MDRAB is monitored by persistent surveillance programs. Because few effective antibiotics are available, clinicians often face serious challenges when treating patients with MDRAB. Therefore, a deep understanding of the resistance mechanisms used by MDRAB can shed light on two possible strategies to combat the dissemination of antimicrobial resistance: stringent infection control and antibiotic treatments, of which colistin-based combination therapy is the mainstream strategy. However, due to the current unsatisfying therapeutic outcomes, there is a great need to develop and evaluate the efficacy of new antibiotics and to understand the role of other potential alternatives, such as antimicrobial peptides, in the treatment of MDRAB infections.
doi:10.12998/wjcc.v2.i12.787
PMCID: PMC4266826  PMID: 25516853
Acinetobacter baumannii; Antibiotic resistance; Epidemiology; Genomics; Infection control
11.  Effects of Carbapenem consumption on the prevalence of Acinetobacter infection in intensive care unit patients 
Background
The consumption of carbapenems has increased worldwide, together with the increase in resistant gram negative bacilli. Subsequently, the prevalence of carbapenem-resistant Acinetobacter infections has increased rapidly and become a significant problem particularly in intensive care unit patients. The aim of the present study was to evaluate the changes in the prevalence of Acinetobacter infection by restricting the consumption of carbapenems in intensive care unit patients.
Methods
This study was conducted between May 1, 2011 and February 28, 2013. The amount of carbapenem consumption and the number of patients with multi-drug resistant Acinetobacter baumannii (MDRAB) isolates during the study period were retrospectively obtained from the records of the patients, who were hospitalized in the intensive care unit. The study period was divided into two periods named as: Carbapenem non-restricted period (CNRP) and carbapenem-restricted period (CRP). During CNRP, no restrictions were made on the use of carbapenems. During CRP, the use of carbapenems was not allowed if there was an alternative to carbapenems. Primary Endpoint: MDRAB infection after ICU admission. The definition of nosocomial infections related to Acinetobacter spp. was based on the criteria of the Center for Disease Control (CDC). The correlation between the amount of carbapenem consumption and the number of infections with MDRAB strains between the two periods were evaluated.
Results
During the study period, a total of 1822 patients’ (1053 patients in CNRP and 769 patients in CRP) records were evaluated retrospectively. A total of 10.82 defined daily dose (DDD/100 ICU days) of anti-pseudomonal carbapenem were used in CNRP, and this figure decreased to 6.95 DDD/100 ICU days in CRP. In the 8-month CNRP, 42 (3.98%) MDRAB-related nosocomial infections were detected, and 14 (1.82%) infections were detected in CRP (p = 0.012).
Conclusion
The prevalence of MDRAB strains isolated in the CNRP was 2.24-fold higher than the prevalence in the CRP. The prevalence of Acinetobacter infections can be reduced by taking strict isolation measures as well as by implementing good antibiotics usage policy.
doi:10.1186/1476-0711-13-7
PMCID: PMC3898784  PMID: 24405720
Carbapenem; Acinetobacter infection; Carbapenem consumption
12.  A Review of Novel Combinations of Colistin and Lipopeptide or Glycopeptide Antibiotics for the Treatment of Multidrug-Resistant Acinetobacter baumannii 
As antibiotic resistance continues to increase among Gram-negative organisms such as Acinetobacter baumannii there is a growing need for novel therapies to overcome these resistance mechanisms. Antibiotics active against multidrug-resistant A. baumannii (MDRAB) are few, and agents in development are primarily active against other multidrug-resistant Gram-negative organisms. The combinations of colistin and antimicrobials such as glycopeptides and lipopeptides are unique potential treatment modalities against MDRAB. For both lipopeptides and glycopeptides in vitro data have demonstrated significant synergy, resulting in rapid bactericidal activity in time-kill curves. Several invertebrate in vivo models have also demonstrated increased survival compared to colistin alone. Currently, very little clinical data have focused on using these combinations for infections caused exclusively by multidrug-resistant Gram-negatives. The combination of vancomycin and colistin has been studied with conflicting results regarding both improved outcomes and risk of nephrotoxicity. Although in vitro and in vivo models have proved promising, further investigation is required to provide clinical data necessary to support the use of these combinations. The objective of this review is to summarize literature currently available for the novel combination of lipopeptides or glycopeptides with colistin for the treatment of A. baumannii, in particular MDRAB.
Electronic supplementary material
The online version of this article (doi:10.1007/s40121-014-0051-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s40121-014-0051-9
PMCID: PMC4269621  PMID: 25475412
Acinetobacter baumannii; Combination therapy; Daptomycin; Vancomycin
13.  Sequence-Based Typing of adeB as a Potential Tool To Identify Intraspecific Groups among Clinical Strains of Multidrug-Resistant Acinetobacter baumannii 
Journal of Clinical Microbiology  2005;43(10):5327-5331.
Sequence analysis of an 850-bp fragment internal to the aspecific drug efflux gene adeB revealed 11 sequence types (STs) among a collection of 50 multidrug-resistant Acinetobacter baumannii (MDRAB) strains, including members of pan-European clones I, II, and III. The delineation of STs conformed with the intraspecific grouping of these strains previously determined by different DNA fingerprinting methods. Larger strain collections need to be screened to further explore the potential of sequence-based adeB typing as a universal tool for the monitoring of MDRAB clones.
doi:10.1128/JCM.43.10.5327-5331.2005
PMCID: PMC1248495  PMID: 16208010
14.  Potent Synergy and Sustained Bactericidal Activity of a Vancomycin-Colistin Combination versus Multidrug-Resistant Strains of Acinetobacter baumannii ▿ †  
Antimicrobial Agents and Chemotherapy  2010;54(12):5316-5322.
Multidrug-resistant Acinetobacter baumannii (MDRAB) presents an increasing challenge to health care. Although colistin has been used as a treatment of last resort, there is concern regarding its potential for toxicity and the emergence of resistance. The mechanism of action of colistin, however, raises the possibility of synergy with compounds that are normally inactive against Gram-negative organisms by virtue of the impermeability of the bacterial outer membrane. This study evaluated the effect of colistin combined with vancomycin on 5 previously characterized epidemic strains and 34 MDRAB clinical isolates by using time-kill assay, microdilution, and Etest methods. For all the isolates, significant synergy was demonstrated by at least one method, with reductions in the MIC of vancomycin from >256 μg/ml to ≤48 μg/ml for all strains after exposure to 0.5 μg/ml colistin. This raises the possibility of the clinical use of this combination for infections due to MDRAB, with the potential for doses lower than those currently used.
doi:10.1128/AAC.00922-10
PMCID: PMC2981237  PMID: 20876375
15.  Rapid Molecular Characterization of Acinetobacter baumannii Clones with rep-PCR and Evaluation of Carbapenemase Genes by New Multiplex PCR in Hospital District of Helsinki and Uusimaa 
PLoS ONE  2014;9(1):e85854.
Multidrug-resistant Acinetobacter baumannii (MDRAB) is an increasing problem worldwide. Prevalence of carbapenem resistance in Acinetobacter spp. due to acquired carbapenemase genes is not known in Finland. The purpose of this study was to examine prevalence and clonal spread of multiresistant A. baumannii group species, and their carbapenemase genes. A total of 55 Acinetobacter isolates were evaluated with repetitive PCR (DiversiLab) to analyse clonality of isolates, in conjunction with antimicrobial susceptibility profile for ampicillin/sulbactam, colistin, imipenem, meropenem, rifampicin and tigecycline. In addition, a new real-time PCR assay, detecting most clinically important carbapenemase genes just in two multiplex reactions, was developed. The assay detects genes for KPC, VIM, IMP, GES-1/-10, OXA-48, NDM, GIM-1, SPM-1, IMI/NMC-A, SME, CMY-10, SFC-1, SIM-1, OXA-23-like, OXA-24/40-like, OXA-58 and ISAbaI-OXA-51-like junction, and allows confident detection of isolates harbouring acquired carbapenemase genes. There was a time-dependent, clonal spread of multiresistant A. baumannii strongly correlating with carbapenamase gene profile, at least in this geographically restricted study material. The new carbapenemase screening assay was able to detect all the genes correctly suggesting it might be suitable for epidemiologic screening purposes in clinical laboratories.
doi:10.1371/journal.pone.0085854
PMCID: PMC3897539  PMID: 24465749
16.  The Clinical Characteristics, Carbapenem Resistance, and Outcome of Acinetobacter Bacteremia According to Genospecies 
PLoS ONE  2013;8(6):e65026.
Background
Few clinical data are available on the relationship between genospecies and outcome of Acinetobacter bacteremia, and the results are inconsistent. We performed this study to evaluate the relationship between genospecies and the outcome of Acinetobacter bacteremia.
Methods
Clinical data from 180 patients who had Acinetobacter bacteremia from 2003 to 2010 were reviewed retrospectively. The genospecies were identified by rpoB gene sequence analysis. The clinical features and outcomes of 90 patients with A. baumannii bacteremia were compared to those of 90 patients with non-baumannii Acinetobacter bacteremia (60 with A. nosocomialis, 17 with Acinetobacter species “close to 13 TU”, 11 with A. pittii, and two with A. calcoaceticus).
Results
A. baumannii bacteremia was associated with intensive care unit-onset, mechanical ventilation, pneumonia, carbapenem resistance, and higher APACHE II scores, compared to non-baumannii Acinetobacter bacteremia (P<0.05). In univariate analyses, age, pneumonia, multidrug resistance, carbapenem resistance, inappropriate empirical antibiotics, higher APACHE II scores, and A. baumannii genospecies were risk factors for mortality (P<0.05). Multivariate analysis revealed A. baumannii genospecies (OR, 3.60; 95% CI, 1.56–8.33), age, pneumonia, and higher APACHE II scores to be independent risk factors for mortality (P<0.05).
Conclusion
A. baumannii genospecies was an independent risk factor for mortality in patients with Acinetobacter bacteremia. Our results emphasize the importance of correct species identification of Acinetobacter blood isolates.
doi:10.1371/journal.pone.0065026
PMCID: PMC3670905  PMID: 23755171
17.  Carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae across a hospital system: impact of post-acute care facilities on dissemination 
Background
Resistance to carbapenems among Acinetobacter baumannii and Klebsiella pneumoniae presents a serious therapeutic and infection control challenge. We describe the epidemiology and genetic basis of carbapenem resistance in A. baumannii and K. pneumoniae in a six-hospital healthcare system in Northeast Ohio.
Methods
Clinical isolates of A. baumannii and K. pneumoniae distributed across the healthcare system were collected from April 2007 to April 2008. Antimicrobial susceptibility testing was performed followed by molecular analysis of carbapenemase genes. Genetic relatedness of isolates was established with repetitive sequence-based PCR (rep-PCR), multilocus PCR followed by electrospray ionization mass spectrometry (PCR/ESI-MS) and PFGE. Clinical characteristics and outcomes of patients were reviewed.
Results
Among 39 isolates of A. baumannii, two predominant genotypes related to European clone II were found. Eighteen isolates contained blaOXA-23, and four isolates possessed blaOXA-24/40. Among 29 K. pneumoniae isolates with decreased susceptibility to carbapenems, two distinct genotypes containing blaKPC-2 or blaKPC-3 were found. Patients with carbapenem-resistant A. baumannii and K. pneumoniae were elderly, possessed multiple co-morbidities, were frequently admitted from and discharged to post-acute care facilities, and experienced prolonged hospital stays (up to 25 days) with a high mortality rate (up to 35%).
Conclusion
In this outbreak of carbapenem-resistant A. baumannii and K. pneumoniae across a healthcare system, we illustrate the important role post-acute care facilities play in the dissemination of multidrug-resistant phenotypes.
doi:10.1093/jac/dkq191
PMCID: PMC2904665  PMID: 20513702
LTCF; LTACH; molecular epidemiology; MLST; PFGE; rep-PCR; KPC
18.  Interleukin-1 receptor antagonist intron 2 variable number of tandem repeats polymorphism and respiratory failure in children with community-acquired pneumonia* 
Objective
To determine whether the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene is associated with lung injury in children with community-acquired pneumonia.
Design
A prospective cohort of children diagnosed with community-acquired pneumonia.
Setting
Two pediatric hospitals.
Patients
Eight hundred fifty pediatric patients with community-acquired pneumonia were enrolled.
Interventions
Genotyping of the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene was performed on DNA isolated from whole blood.
Measurements and Main Results
The requirement for positive pressure ventilation or the diagnosis of acute lung injury or acute respiratory distress syndrome were the main outcomes of the study. Children (14 days–19 yrs) with community-acquired pneumonia (850) were enrolled; analysis was limited to African American (515) and Caucasian (232) patients. Of the 82 patients requiring positive pressure ventilation, 44 were diagnosed with acute lung injury or acute respiratory distress syndrome. Multivariate logistic regression analyses indicated that children without a copy of the A1 allele of the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene were more likely to need positive pressure ventilation compared to those with one or two copies of this allele (odds ratio = 2.65, confidence interval, 1.02– 6.90). In addition, the absence of the A1 allele also appeared to be associated with the development of community-acquired pneumonia–induced acute lung injury/acute respiratory distress syndrome (odds ratio = 3.1, confidence interval, 0.99 –9.67).
Conclusions
In children with community-acquired pneumonia, absence of the A1 allele at the interleukin-1 receptor antagonist intron 2 polymorphic site is associated with increased risk for more severe lung injury, as measured by the need for positive pressure ventilation or the development of acute lung injury or acute respiratory distress syndrome. Conversely, presence of the A1 allele is associated with decreased risk for more severe lung injury in this patient population.
doi:10.1097/PCC.0b013e31818d32f1
PMCID: PMC2760301  PMID: 18838927
interleukin-1 receptor antagonist; genetic polymorphisms; pediatrics; lung injury; acute respiratory distress syndrome
19.  Identification of an Acinetobacter baumannii Zinc Acquisition System that Facilitates Resistance to Calprotectin-mediated Zinc Sequestration 
PLoS Pathogens  2012;8(12):e1003068.
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.
Author Summary
Acinetobacter baumannii is a bacterium responsible for an increasing number of infections in the hospital setting. These infections are particularly challenging because most strains of A. baumannii are resistant to commonly used antibiotics. Unfortunately, there is relatively little known about this organism and how it causes disease, making it difficult to identify new drug targets. In order to address this problem we examined the role for nutrient manganese (Mn) and zinc (Zn) in A. baumannii infections. We have determined that the host protein, calprotectin (CP), contributes to defense against A. baumannii pneumonia through chelation of nutrient Mn and Zn. Moreover, employing purified calprotectin as a probe allowed us to identify a Zn acquisition system in A. baumannii that is required for efficient Zn uptake in vitro and full pathogenesis in vivo. Finally, we demonstrate that inhibiting Zn acquisition can reverse antibiotic resistance mechanisms that rely on Zn-dependent enzymes. Taken together, these results demonstrate the importance of Zn acquisition to A. baumannii pathogenesis and antibiotic resistance, establishing Zn acquisition as a potential target for therapeutic development.
doi:10.1371/journal.ppat.1003068
PMCID: PMC3516566  PMID: 23236280
20.  Incidence, risk stratification, antibiogram of pathogens isolated and clinical outcome of ventilator associated pneumonia 
Background:
The initial empirical therapy of Ventilator Associated Pneumonia (VAP) modified based on the knowledge of local microbiological data is associated with decreased morbidity and mortality. The objective was to find the incidence and risk factors associated with VAP, the implicated pathogens and their susceptibility pattern as well as to assess the final clinical outcome in VAP.
Materials and Methods:
This was a prospective cohort study of 107 patients taken on ventilatory support for two or more days and those not suffering from pneumonia prior were to be taken on ventilator. The study was done over a period of one year. VAP was diagnosed using clinical pulmonary infection score of >6. The mortality, incidence of VAP, frequency of different pathogens isolated, their antibiotic sensitivity pattern, duration of mechanical ventilation and duration of hospital stay were assessed.
Statistical Analysis:
Univariate analysis, χ2 test and paired t-test.
Results:
The incidence of VAP was 28.04%. Mortality in VAP group was 46.67%, while in the non-VAP group was 27.28%. High APACHE II score was associated with a high mortality rate as well as increased incidence of VAP. The most common organisms isolated from endotracheal aspirate of patients who developed VAP were Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae and Acinetobacter baumannii. Most strains of Pseudomonas (55.56%) were resistant to commonly used beta-lactam antibiotics known to be effective against Pseudomonas. All strains of Staphylococcus aureus were MRSA and most isolates of K. pneumoniae (85.71%) were extended-spectrum beta-lactamase producing. About 50% isolates of Acinetobacter were resistant to carbapenems. Mortality was highest for infections caused by A. baumannii (83.33%) and K. pneumoniae (71.42%).
Conclusions:
APACHE II score can be used to stratify the risk of development of VAP and overall risk of mortality. Drug-resistant strains of various organisms are an important cause of VAP in our setting.
doi:10.4103/0972-5229.83015
PMCID: PMC3145311  PMID: 21814373
APACHE II score; clinical pulmonary infection score; mechanical ventilation; ventilator associated pneumonia
21.  Controlled Performance Evaluation of the DiversiLab Repetitive-Sequence-Based Genotyping System for Typing Multidrug-Resistant Health Care-Associated Bacterial Pathogens▿ 
Journal of Clinical Microbiology  2011;49(10):3616-3620.
Fast, reliable, and versatile typing tools are essential to differentiate among related bacterial strains for epidemiological investigation and surveillance of health care-associated infection with multidrug-resistant (MDR) pathogens. The DiversiLab (DL) system is a semiautomated repetitive-sequence-based PCR system designed for rapid genotyping. The DL system performance was assessed by comparing its reproducibility, typeability, discriminatory power, and concordance with those of pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) and by assessing its epidemiological concordance on well-characterized MDR bacterial strains (n = 165). These included vanA Enterococcus faecium, extended-spectrum β-lactamase (ESBL)-producing strains of Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii, and ESBL- or metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa strains. The DL system showed very good performance for E. faecium and K. pneumoniae and good performance for other species, except for a discrimination index of <95% for A. baumannii and E. coli (93.9% and 93.5%, respectively) and incomplete concordance with MLST for P. aeruginosa (78.6%) and E. coli (97.0%). Occasional violations of MLST assignment by DL types were noted for E. coli. Complete epidemiological concordance was observed for all pathogens, as all outbreak-associated strains clustered in identical DL types that were distinct from those of unrelated strains. In conclusion, the DL system showed good to excellent performance, making it a reliable typing tool for investigation of outbreaks caused by study pathogens, even though it was generally less discriminating than PFGE analysis. For E. coli and P. aeruginosa, MLST cannot be reliably inferred from DL type due to phylogenetic group violation or discordance.
doi:10.1128/JCM.00528-11
PMCID: PMC3187349  PMID: 21813717
22.  A comparison of microbiology and demographics among patients with healthcare-associated, hospital-acquired, and ventilator-associated pneumonia: a retrospective analysis of 1184 patients from a large, international study 
BMC Infectious Diseases  2013;13:561.
Background
Acceptance of healthcare-associated pneumonia (HCAP) as an entity and the associated risk of infection by potentially multidrug-resistant (MDR) organisms such as methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas and Acinetobacter have been debated. We therefore compared patients with HCAP, hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) enrolled in a trial comparing linezolid with vancomycin for treatment of pneumonia.
Methods
The analysis included all patients who received study drug. HCAP was defined as pneumonia occurring < 48 hours into hospitalization and acquired in a long-term care, subacute, or intermediate health care facility; following recent hospitalization; or after chronic dialysis.
Results
Data from 1184 patients (HCAP = 199, HAP = 379, VAP = 606) were analyzed. Compared with HAP and VAP patients, those with HCAP were older, had slightly higher severity scores, and were more likely to have comorbidities. Pseudomonas aeruginosa was the most common gram-negative organism isolated in all pneumonia classes [HCAP, 22/199 (11.1%); HAP, 28/379 (7.4%); VAP, 57/606 (9.4%); p = 0.311]. Acinetobacter spp. were also found with similar frequencies across pneumonia groups. To address potential enrollment bias toward patients with MRSA pneumonia, we grouped patients by presence or absence of MRSA and found little difference in frequencies of Pseudomonas and Acinetobacter.
Conclusions
In this population of pneumonia patients, the frequencies of MDR gram-negative pathogens were similar among patients with HCAP, HAP, or VAP. Our data support inclusion of HCAP within nosocomial pneumonia guidelines and the recommendation that empiric antibiotic regimens for HCAP should be similar to those for HAP and VAP.
doi:10.1186/1471-2334-13-561
PMCID: PMC4222644  PMID: 24279701
Nosocomial pneumonia; Healthcare-associated pneumonia; Intensive care; Hospital-acquired pneumonia; Ventilator-associated pneumonia
23.  Use of Vaporized Hydrogen Peroxide Decontamination during an Outbreak of Multidrug-Resistant Acinetobacter baumannii Infection at a Long-Term Acute Care Hospital 
OBJECTIVES
To describe vaporized hydrogen peroxide (VHP) as an adjuvant in the control of multidrug-resistant (MDR) Acinetobacter baumannii infection in a long-term acute care hospital (LTACH) and to describe the risk factors for acquisition of MDR A. baumannii infection in the LTACH population.
DESIGN
Outbreak investigation, case-control study, and before-after intervention trial.
SETTING
A 54-bed LTACH affiliated with a tertiary care center in northeastern Ohio.
METHODS
Investigation of outbreak with clinical and environmental cultures, antimicrobial susceptibility testing, polymerase chain reaction assay of repetitive chromosomal elements to type strains, and case-control study; and intervention consisting of comprehensive infection control measures and VHP environmental decontamination.
RESULTS
Thirteen patients infected or colonized with MDR A. baumannii were identified from January 2008 through June 2008. By susceptibility testing, 10 (77%) of the 13 isolates were carbapenem-resistant. MDR A. baumannii was found in wound samples, blood, sputum, and urine. Wounds were identified as a risk factor for MDR A. baumannii colonization. Ventilator–associated pneumonia was the most common clinical syndrome caused by the pathogen, and the associated mortality was 14% (2 of the 13 case patients died). MDR A. baumannii was found in 8 of 93 environmental samples, including patient rooms and a wound care cart; environmental and clinical cultures were genetically related. Environmental cultures were negative immediately after VHP decontamination and both 24 hours and 1 week after VHP decontamination. Nosocomial acquisition of the pathogen in the LTACH ceased after VHP intervention. When patients colonized with MDR A. baumannii reoccupied rooms, environmental contamination recurred.
CONCLUSION
Environmental decontamination using VHP combined with comprehensive infection control measures interrupted nosocomial transmission of MDR A. baumannii in an LTACH. The application of this novel approach to halt the transmission of MDR A. baumannii warrants further investigation.
doi:10.1086/657139
PMCID: PMC3731999  PMID: 20973723
24.  Multidrug resistant Acinetobacter baumannii: a descriptive study in a city hospital 
BMC Infectious Diseases  2010;10:196.
Background
Multidrug resistant Acinetobacter baumannii, (MRAB) is an important cause of hospital acquired infection. The purpose of this study is to determine the risk factors for MRAB in a city hospital patient population.
Methods
This study is a retrospective review of a city hospital epidemiology data base and includes 247 isolates of Acinetobacter baumannii (AB) from 164 patients. Multidrug resistant Acinetobacter baumannii was defined as resistance to more than three classes of antibiotics. Using the non-MRAB isolates as the control group, the risk factors for the acquisition of MRAB were determined.
Results
Of the 247 AB isolates 72% (177) were multidrug resistant. Fifty-eight percent (143/247) of isolates were highly resistant (resistant to imipenem, amikacin, and ampicillin-sulbactam). Of the 37 patients who died with Acinetobacter colonization/infection, 32 (86%) patients had the organism recovered from the respiratory tract. The factors which were found to be significantly associated (p ≤ 0.05) with multidrug resistance include the recovery of AB from multiple sites, mechanical ventilation, previous antibiotic exposure, and the presence of neurologic impairment. Multidrug resistant Acinetobacter was associated with significant mortality when compared with sensitive strains (p ≤ 0.01). When surgical patients (N = 75) were considered separately, mechanical ventilation and multiple isolates remained the factors significantly associated with the development of multidrug resistant Acinetobacter. Among surgical patients 46/75 (61%) grew a multidrug resistant strain of AB and 37/75 (40%) were resistant to all commonly used antibiotics including aminoglycosides, cephalosporins, carbepenems, extended spectrum penicillins, and quinolones. Thirty-five percent of the surgical patients had AB cultured from multiple sites and 57% of the Acinetobacter isolates were associated with a co-infecting organism, usually a Staphylococcus or Pseudomonas. As in medical patients, the isolation of Acinetobacter from multiple sites and the need for mechanical ventilation were significantly associated with the development of MRAB.
Conclusions
The factors significantly associated with MRAB in both the general patient population and surgical patients were mechanical ventilation and the recovery of Acinetobacter from multiple anatomic sites. Previous antibiotic use and neurologic impairment were significant factors in medical patients. Colonization or infection with MRAB is associated with increased mortality.
doi:10.1186/1471-2334-10-196
PMCID: PMC2909240  PMID: 20609238
25.  Occupational Transmission of Acinetobacter baumannii from a United States Serviceman Wounded in Iraq to a Health Care Worker 
Background
Acinetobacter baumannii is increasingly recognized as being a significant pathogen associated with nosocomial outbreaks in both civilian and military treatment facilities. Current analyses of these outbreaks frequently describe patient-to-patient transmission. To date, occupational transmission of A. baumannii from a patient to a health care worker (HCW) has not been reported. We initiated an investigation of an HCW with a complicated case of A. baumannii pneumonia to determine whether a link existed between her illness and A. baumannii–infected patients in a military treatment facility who had been entrusted to her care.
Methods
Pulsed-field gel electrophoresis and polymerase chain reaction/electrospray ionization mass spectrometry, a form of multilocus sequencing typing, were done to determine clonality. To further characterize the isolates, we performed a genetic analysis of resistance determinants.
Results and Conclusions
A “look-back” analysis revealed that the multidrug resistant A. baumannii recovered from the HCW and from a patient in her care were indistinguishable by pulsed-field gel electrophoresis. In addition, polymerase chain reaction/electrospray ionization mass spectrometry indicated that the isolates were similar to strains of A. baumannii derived from European clone type II (Walter Reed Army Medical Center strain type 11). The exposure of the HCW to the index patient lasted for only 30 min and involved endotracheal suctioning without use of an HCW mask. An examination of 90 A. baumannii isolates collected during this investigation showed that 2 major and multiple minor clone types were present and that the isolates from the HCW and from the index patient were the most prevalent clone type. Occupational transmission likely occurred in the hospital; HCWs caring for patients infected with A. baumannii should be aware of this potential mode of infection spread.
doi:10.1086/589247
PMCID: PMC4074882  PMID: 18611162

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