Sequential intraventricular injection of tigecycline and polymyxin B in the treatment of intracranial Acinetobacter baumannii infection after trauma: a case report and review of the literature.

BACKGROUND: Intracranial infection after craniotomy is one of the most serious postoperative complications, especially multidrug-resistant (MDR) or extensively drug-resistant (XDR) bacterial meningitis, and strongly affects the prognosis of patients. Current treatment experience regarding these infections is scarce. CASE PRESENTATION: We report a case of severe intracranial infection of XDR Acinetobacter baumannii (A. baumannii) that was treated by intravenous (IV) injection, sequential intraventricular (IVT) injection of tigecycline and polymyxin B, and other anti-infective drugs. Good results were obtained, and the patient was eventually discharged from the hospital. This case is characterized by intracranial infection. CONCLUSIONS: The polymyxin B IV + IVT pathway is an ideal treatment strategy for XDR A. baumannii. The tigecycline IVT pathway is also a safe treatment option.

Case series: Fulminant community-acquired Acinetobacter pneumonia.

Acinetobacter infection, especially the drug-resistant strain, is a common cause of nosocomial infection. However, community-acquired Acinetobacter infection is uncommon. We reported three cases of community-acquired Acinetobacter pneumonia. All three cases had histories of regular home-brewed alcohol consumption presented with severe acute respiratory symptoms requiring ventilatory support and had low total white cell count. They succumbed to the illness within 2 to 10 days of admission. They had positive blood or endotracheal aspirate cultures of sensitive-strain Acinetobacter sp. which was only sensitive to high dose sulbactam. Early recognition and correct antibiotic can help reduce mortality.

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

PURPOSE: We aimed to characterize clinical manifestations of the patients with bacteremia due to community-acquired Acinetobacter baumannii and evaluate the outcomes of these patients. METHODS: We 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. RESULTS: There 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. CONCLUSIONS: Patients 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.

A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X during Acinetobacter baumannii Infection.

Coagulation and inflammation are interconnected, suggesting that coagulation plays a key role in the inflammatory response to pathogens. A phenome-wide association study (PheWAS) was used to identify clinical phenotypes of patients with a polymorphism in coagulation factor X. Patients with this single nucleotide polymorphism (SNP) were more likely to be hospitalized with hemostatic and infection-related disorders, suggesting that factor X contributes to the immune response to infection. To investigate this, we modeled infections by human pathogens in a mouse model of factor X deficiency. Factor X-deficient mice were protected from systemic Acinetobacter baumannii infection, suggesting that factor X plays a role in the immune response to A. baumannii Factor X deficiency was associated with reduced cytokine and chemokine production and alterations in immune cell population during infection: factor X-deficient mice demonstrated increased abundance of neutrophils, macrophages, and effector T cells. Together, these results suggest that factor X activity is associated with an inefficient immune response and contributes to the pathology of A. baumannii infection.

Pneumonia infection in mice reveals the involvement of the feoA gene in the pathogenesis of Acinetobacter baumannii.

Acinetobacter baumannii has emerged in the last decade as an important nosocomial pathogen. To identify genes involved in the course of a pneumonia infection, gene expression profiles were obtained from A. baumannii ATCC 17978 grown in mouse infected lungs and in culture medium. Gene expression analysis allowed us to determine a gene, the A1S_0242 gene (feoA), over-expressed during the pneumonia infection. In the present work, we evaluate the role of this gene, involved in iron uptake. The inactivation of the A1S_0242 gene resulted in an increase susceptibility to oxidative stress and a decrease in biofilm formation, in adherence to A549 cells and in fitness. In addition, infection of G. mellonella and pneumonia in mice showed that the virulence of the Δ0242 mutant was significantly attenuated. Data presented in this work indicated that the A1S_0242 gene from A. baumannii ATCC 17978 strain plays a role in fitness, adhesion, biofilm formation, growth, and, definitively, in virulence. Taken together, these observations show the implication of the feoA gene plays in the pathogenesis of A. baumannii and highlight its value as a potential therapeutic target.

Impact of reduced tigecycline susceptibility on clinical outcomes of Acinetobacter bacteremia.

The higher 14-day mortality rate for patients with Acinetobacter bacteremia receiving tigecycline appropriately compared to other appropriate antibiotics (36.4% versus 14.2%, P = 0.028) was due to the poor effect of tigecycline for isolates with a minimum inhibitory concentration of 2 µg/mL (63.6% of 11 versus 14.2% of 127, P = 0.001).

Prolonged and high dosage of tigecycline - successful treatment of spondylodiscitis caused by multidrug-resistant Acinetobacter baumannii: a case report.

BACKGROUND: The incidence of infectious spondylodiscitis has been increasing over the last few years. This reflects the expanding elderly and immunocompromised populations and the rising implementation of invasive spinal procedures. Infection may be inoculated into the disc space directly during invasive spinal procedures. Osteomyelitis caused by Acinetobacter species is rare and mainly caused by multidrug-resistant strains. CASE PRESENTATION: We present the case of a 72-year-old Greek woman with postoperative spondylodiscitis caused by a multidrug-resistant Acinetobacter baumannii strain that was successfully treated, after she declined surgical treatment, with prolonged and high dosage of tigecycline. She received intravenously administered tigecycline 200 mg per day for 60 days and then 100 mg per day for a total of 102 days and was infection-free. CONCLUSIONS: We reviewed the literature on the role of Acinetobacter baumannii as a cause of osteomyelitis, emphasizing the difficulty of treatment and the potential role of tigecycline in conservative treatment of the infection. We believe that 102 days in total is the longest time that any patient has received tigecycline in the literature, thus our patient is a unique case of successful treatment of spondylodiscitis.

Risk Factors, Clinical Presentation, and Outcome of Acinetobacter baumannii Bacteremia.

Infections caused by Acinetobacter baumannii (AB), an increasingly prevalent nosocomial pathogen, have been associated with high morbidity and mortality. We conducted this study to analyze the clinical features, outcomes, and factors influencing the survival of patients with AB bacteremia. We retrospectively examined the medical records of all patients developing AB bacteremia during their hospital stay at a tertiary care hospital in Beirut between 2010 and 2015. Ninety episodes of AB bacteremia were documented in eighty-five patients. Univariate analysis showed that prior exposure to high dose steroids, diabetes mellitus, mechanical ventilation, prior use of colistin and tigecycline, presence of septic shock, and critical care unit stay were associated with a poor outcome. High dose steroids and presence of septic shock were significant on multivariate analysis. Crude mortality rate was 63.5%. 70.3% of the deaths were attributed to the bacteremia. On acquisition, 39 patients had septicemia. Despite high index of suspicion and initiation of colistin and/or tigecycline in 18/39 patients, a grim outcome could not be averted and 37 patients died within 2.16 days. Seven patients had transient benign bacteremia; three of which were treated with removal of the line. The remaining four did not receive any antibiotics due to withdrawal of care and died within 26.25 days of acquiring the bacteremia, with no signs of persistent infection on follow up. A prolonged hospital stay is frequently associated with loss of functionality, and steroid and antibiotic exposure. These factors seem to impact the mortality of AB bacteremia, a disease with high mortality rate and limited therapeutic options.

The Secrets of Acinetobacter Secretion.

Infections caused by the bacterial pathogen Acinetobacter baumannii are a mounting concern for healthcare practitioners as widespread antibiotic resistance continues to limit therapeutic treatment options. The biological processes used by A. baumannii to cause disease are not well defined, but recent research has indicated that secreted proteins may play a major role. A variety of mechanisms have now been shown to contribute to protein secretion by A. baumannii and other pathogenic species of Acinetobacter, including a type II secretion system (T2SS), a type VI secretion system (T6SS), autotransporter, and outer membrane vesicles (OMVs). In this review, we summarize the current knowledge of secretion systems in Acinetobacter species, and highlight their unique aspects that contribute to the pathogenicity and persistence of these emerging pathogens.

Analysis of clinical and microbiological data on Acinetobacter baumannii strains assist the preauthorization of antibiotics at the patient level for an effective antibiotic stewardship program.

Drug resistant Acinetobacter baumannii (A. baumannii) poses serious treatment challenges and is on the rise worldwide. The Infectious Diseases Society of America/Society for Healthcare Epidemiology of America recommends preauthorization of antibiotics to ensure successful antibiotic stewardship programs (ASWPs). This study estimates and analyzes the microbiological and clinical characteristics of A. baumanii strains with differentiating criteria for sepsis versus colonization, in order to support preauthorization and assist ASWPs at the patient level. A retrospective observational study was performed from 2008 to 2014. The clinical and microbiological characteristics of A. baumannii strains were correlated to assess pathogenic status and antibiotic resistance patterns. A flow chart was produced to differentiate between sepsis and colonization amongst patient groups. A. baumannii was cultured in 2656 cases, with a prevalence of 0.9-2.4% during 7 years study periods. There was a statistically significant difference between the sepsis and colonization groups (P=0.02). Sepsis accounted for 37-51% of A. baumanii isolates and colonisation for 49-63% (P=<0.01). Multidrug resistant (MDR), extensive drug resistant (XDR) and pandrug resistant (PDR) A. baumannii was detected in 53-60%, 1-19% and 1% of cultures in the sepsis group, and 75%, 8-23% and 1% in the colonized group. There was a high percentage of polymicrobial infection in the sepsis group and pure growth was not always significant for sepsis. Cases of MDR and XDR A. baumannii increased over the seven-year study, while PDR strains emerged. For a successful ASWP, both clinical and microbiological information should be interpreted when establishing preauthorization/decision to treat.

Host-Microbe Protein Interactions during Bacterial Infection.

Interspecies protein-protein interactions are essential mediators of infection. While bacterial proteins required for host cell invasion and infection can be identified through bacterial mutant library screens, information about host target proteins and interspecies complex structures has been more difficult to acquire. Using an unbiased chemical crosslinking/mass spectrometry approach, we identified interspecies protein-protein interactions in human lung epithelial cells infected with Acinetobacter baumannii. These efforts resulted in identification of 3,076 crosslinked peptide pairs and 46 interspecies protein-protein interactions. Most notably, the key A. baumannii virulence factor, OmpA, was identified as crosslinked to host proteins involved in desmosomes, specialized structures that mediate host cell-to-cell adhesion. Co-immunoprecipitation and transposon mutant experiments were used to verify these interactions and demonstrate relevance for host cell invasion and acute murine lung infection. These results shed new light on A. baumannii-host protein interactions and their structural features, and the presented approach is generally applicable to other systems.

Population pharmacokinetic-pharmacodynamic target attainment analysis of sulbactam in patients with impaired renal function: dosing considerations for Acinetobacter baumannii infections.

UNLABELLED: This study aimed to perform a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of sulbactam against Acinetobacter baumannii in patients with impaired renal function. The PK data (188 plasma samples and 27 urine samples) were modeled simultaneously. The mean population parameters were CLr (l/h) = 0.0792 × CLcr (ml/min), CLnr (l/h) = 2.35, Vc (l) = 12.2, Q (l/h) = 4.68 and Vp (l) = 4.44, where CLr and CLnr are the renal and non-renal clearances, Vc and Vp are the distribution volumes of the central and peripheral compartments and Q is intercompartmental clearance. The creatinine clearance (CLcr) was the most significant covariate. The determined MIC of sulbactam against A. baumannii clinical isolates (n = 27) was 0.75-6.0 µg/ml with MIC50 and MIC90 of 1 and 4 µg/ml, respectively. For sulbactam regimens, a Monte Carlo simulation estimated the probabilities of attaining the bactericidal target (60% of the time above the MIC) and determined the PK-PD breakpoints (the highest MICs at which the probabilities were 90% or more). In a patient with a CLcr of 15 ml/min, a regimen of 1 g twice daily achieved a 90% or more probability against the A. baumannii isolate population; however, 2 g four times daily was needed for a 90% or more probability in a patient with a CLcr of 90 ml/min. The results of the PK-PD target attainment analysis are useful when choosing the sulbactam regimen based on the CLcr of the patient and the susceptibility of A. baumannii. REGISTRATION NUMBER: UMIN000007356.

Epidemiologic and clinical impact of Acinetobacter baumannii colonization and infection: a reappraisal.

Acinetobacter baumannii is one of the most important antibiotic-resistant nosocomial bacteria. We investigated changes in the clinical and molecular epidemiology of A. baumannii over a 10-year period. We compared the data from 2 prospective multicenter cohort studies in Spain, one performed in 2000 (183 patients) and one in 2010 (246 patients), which included consecutive patients infected or colonized by A. baumannii. Molecular typing was performed by repetitive extragenic palindromic polymerase chain reaction (REP-PCR), pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST). The incidence density of A. baumannii colonization or infection increased significantly from 0.14 in 2000 to 0.52 in 2010 in medical services (p < 0.001). The number of non-nosocomial health care-associated cases increased from 1.2% to 14.2%, respectively (p < 0.001). Previous exposure to carbapenems increased in 2010 (16.9% in 2000 vs 27.3% in 2010, p = 0.03). The drugs most frequently used for definitive treatment of patients with infections were carbapenems in 2000 (45%) and colistin in 2010 (50.3%). There was molecular-typing evidence of an increase in the frequency of A. baumannii acquisition in non-intensive care unit wards in 2010 (7.6% in 2000 vs 19.2% in 2010, p = 0.01). By MSLT, the ST2 clonal group predominated and increased in 2010. This epidemic clonal group was more frequently resistant to imipenem and was associated with an increased risk of sepsis, although not with severe sepsis or mortality. Some significant changes were noted in the epidemiology of A. baumannii, which is increasingly affecting patients admitted to conventional wards and is also the cause of non-nosocomial health care-associated infections. Epidemic clones seem to combine antimicrobial resistance and the ability to spread, while maintaining their clinical virulence.

Pathogenicity of ocular isolates of Acinetobacter baumannii in a mouse model of bacterial endophthalmitis.

PURPOSE: To determine the virulence properties of ocular isolates of Acinetobacter baumannii in causing endophthalmitis in a mouse model. METHODS: Endophthalmitis was induced by intravitreal injections of the bacteria into C57BL/6 (B6) mouse eyes. The disease progression was monitored by ophthalmoscopic, electroretinography (ERG), histologic, cell death (TUNEL labeling), and microbiological parameters. The expression of cytokines/chemokines was checked by quantitative RT-PCR (qRT-PCR) and ELISA. Flow cytometry was used to determine cellular infiltration. The role of neutrophils was determined using neutropenic mice. The virulence traits (biofilm formation, adherence, and cytotoxicity) of the ocular isolates were tested using corneal epithelial cells. RESULTS: Among the three clinical isolates and a standard ATCC 19606 strain tested, a biofilm producing multidrug resistant (MDR) strain of A. baumannii AB12 caused severe endophthalmitis (100% destruction of the eyes) leading to the loss of retinal function as assessed by ERG analysis. Elevated levels of inflammatory mediators (TNF-α, IL-1ß, CXCL2, and IL-6) were detected in AB12-infected eyes. Histologic and TUNEL staining revealed increased retinal cell death and the flow cytometry data showed the presence of inflammatory cells, primarily neutrophils (CD45(+)/Ly6G(+)). Neutropenic mice showed an increased bacterial burden, reduced inflammatory response, and severe tissue destruction. CONCLUSIONS: These results indicate that A. baumannii causes severe intraocular inflammation and retinal damage. Furthermore, neutrophils play an important role in the pathogenesis of A. baumannii endophthalmitis.

Ultraviolet C light for Acinetobacter baumannii wound infections in mice: potential use for battlefield wound decontamination?

BACKGROUND: Since the beginning of the conflicts in the Middle East, US Army physicians have noted a high rate of multidrug-resistant Acinetobacter baumannii infections among US soldiers wounded and initially treated in Iraq. In this study, we investigated the use of ultraviolet C (UVC) light for prevention of multidrug-resistant A. baumannii wound infections using mouse models. METHODS: Partial-thickness skin abrasions and full-thickness burns in mice were infected with a multidrug-resistant A. baumannii isolate recovered from a wounded US soldier deployed to Iraq. The luxCDABE operon, which was contained in plasmid pMF 385, was cloned into the A. baumannii strain. This allowed real-time monitoring of the extent of infection in mice using bioluminescence imaging. UVC light was delivered to the mouse wounds at 30 minutes after the inoculation of A. baumannii. Groups of infected mouse wounds without being exposed to UVC served as the controls. RESULTS: In vitro studies demonstrated that A. baumannii cells were inactivated at UVC exposures much lower than those needed for a similar effect on mammalian cells. It was observed in animal studies that UVC (3.24 J/cm(2) for abrasions and 2.59 J/cm(2) for burns) significantly reduced the bacterial burdens in UVC-treated wounds by approximately 10-fold compared with nontreated controls (p = 0.004 for abrasions, p = 0.019 for burns). DNA lesions were observed by immunofluorescence in mouse skin abrasions immediately after a UVC exposure of 3.24 J/cm(2); however, the lesions were extensively repaired within 72 hours. CONCLUSION: These results suggested that UVC may be useful in preventing combat-related wound infections.

Clinical impacts of a single clone (sequence type 92) of multidrug-resistant Acinetobacter baumannii in intensive care units.

The clinical outcomes of patients infected with a single clone of an multidrug-resistant (MDR) strain of Acinetobacter baumannii were investigated. A matched comparative cohort study was conducted in a tertiary hospital in Korea. Thirty patients infected with single clone of MDR A. baumannii admitted to two intensive care units (ICUs) were matched to 30 control patients without A. baumannii, while controlling for concomitant diseases and severity of illness. All analyzed MDR A. baumannii isolates were identified as sequence type (ST) 92. In-hospital and in-ICU mortality rates did not differ significantly between the cases and controls (p=0.795 vs. p=0.796). Multivariate analysis demonstrated that MDR A. baumannii ST92 infection was the independent risk factor for prolonged hospital stay (odds ratio [OR] 13.12, 95% confidence interval [CI] 3.06-56.19, p=0.001), prolonged ICU stay (OR 9.66, 95% CI 2.73-34.13, p<0.001), and prolonged mechanical ventilation (OR 8.63, 95% CI 2.21-33.68, p=0.002). These findings indicate that MDR A. baumannii ST92 infection results in adverse outcomes of patients, and strict adherence to infection controls in ICUs should be encouraged.

Carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii: assessing their impact on organ transplantation.

PURPOSE OF REVIEW: This review highlights the impact of carbapenem-resistant Enterobacteriaceae and carbapenem-resistant Acinetobacter baumannii on patients who have undergone organ transplantation and explores both available and potential agents to treat infections caused by these multidrug-resistant (MDR) pathogens. RECENT FINDINGS: Few antimicrobials exist to treat carbapenem-resistant Gram-negative infections, and resistance to salvage therapies is escalating. Organ transplantation appears to be a risk factor for infections with Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae. Isolation of these MDR bacteria is increasing and may be associated with allograft failure and mortality. In the majority of cases, aminoglycosides, polymyxins, and tigecycline have been employed to treat these infections. Anecdotal successes exist but these antibiotics may be unreliable. Few novel agents are in development. SUMMARY: Bacterial infections remain a leading cause of posttransplantation morbidity and mortality. Carbapenem resistance is a significant threat to allograft and patient survival. With few antimicrobials being developed, transplant centers may be forced to make decisions regarding surveillance, empiric antimicrobial regimens, and transplant candidacy in the setting of carriage of MDR pathogens. There is an urgent need for collaborative studies to address the clinical impact of these infections on transplantation.

Nosocomial imipenem-resistant Acinetobacter baumannii infections: epidemiology and risk factors.

The incidence, clinical characteristics, risk factors, antimicrobial susceptibility, and outcomes of nosocomial imipenem-resistant A. baumannii (IRAB) infections during a 5-y period (2003-2007) were retrospectively analyzed. A total of 720 patients with 925 episodes of A. baumannii infection were included in the study. A. baumannii infections were seen mostly in intensive care units. The incidence was 6.2 per 1000 admissions. The most common infections were pneumonias and bloodstream infections. Imipenem resistance among Acinetobacter strains increased significantly each y of the study (from 43.3% to 72.9%). Mortality was related to the presence of imipenem resistance, stay in intensive care unit, female gender, old age, and pneumonia. Haemodialysis, malignancy, and mechanical ventilation were significant risk factors for IRAB infections. Imipenem resistance was higher in strains isolated from patients with pneumonia. IRAB strains showed higher resistance rates to other antibiotics than imipenem-susceptible strains. The most active antimicrobial agents against A. baumannii were cefoperazone-sulbactam and netilmicin. The incidence of A. baumannii infections and imipenem resistance increased during the study period. IRAB infections should be considered in patients on mechanical ventilation and haemodialysis and in patients with malignancies.

Multidrug-resistant Acinetobacter baumannii ventriculitis: successful treatment with intraventricular colistin.

Acinetobacter baumannii has emerged as an important nosocomial pathogen that can cause a multitude of severe infections. In neurosurgical patients the usual presentation is ventriculitis associated with external ventricular drainage. Carbapenems have been considered the gold standard for the treatment of Acinetobacter baumannii ventriculitis, but resistant isolates are increasing worldwide, reducing the therapeutic options. In many cases polymyxins are the only possible alternative, but their poor blood-brain barrier penetration could require them to be directly administered intraventricularly and clinical experience with this route is limited. We review the literature concerning intraventricular use of colistin (polymyxin E) for A. baumannii ventriculitis and add three cases successfully treated with this method. Our experience suggests that intraventricular colistin is a potentially effective and safe therapy for the treatment of multidrug-resistant A. baumannii central nervous system infections.