Post-treatment with the PPAR-γ agonist pioglitazone inhibits inflammation and bacterial growth during Klebsiella pneumonia.

Agonists of peroxisome proliferator-activated receptor (PPAR)-γ have been suggested as potential adjuvant therapy in bacterial pneumonia because of their capacity to inhibit inflammation and enhance bacterial clearance. Previous studies only assessed the effects of pretreatment with these compounds, thereby bearing less relevance for the clinical scenario. Moreover, PPAR-γ agonists have not been studied in pneumonia caused by Klebsiella pneumoniae, a common human respiratory pathogen of which antibiotic treatment is hampered by increasing antimicrobial resistance. Here we show that administration of the PPAR-γ agonist pioglitazone 6 or 8 h after infection of mice with a highly virulent strain of Klebsiella pneumoniae via the airways results in reduced cytokine and myeloperoxidase levels in the lungs at 24 h after infection, as well as reduced bacterial growth in the lungs and decreased dissemination to distant organs at 42 h post-infection. These results suggest that pioglitazone may be an interesting agent in the treatment of Klebsiella pneumonia.

Pathophysiological effects of Klebsiella pneumoniae infection on Galleria mellonella as an invertebrate model organism.

Klebsiella pneumoniae is an important human pathogen causing urinary tract infections and pneumonia. Due to the increase in resistant strains and being an opportunistic pathogen, it is very important to determine the virulence process, the cellular damage it causes in the host and the immunological response level of the host. In this study, invertebrate infection model Galleria mellonella larvae were used to investigate cellular damage, antioxidant response and changes in biochemical parameters due to K. pneumoniae infection. The activity of cell damage indicators alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase increased in hemolymph of G. mellonella larvae due to K. pneumoniae virulence. Creatine kinase, alkaline phosphatase, gamma glutamyl transferase and amylase activities were increased to regulate the disrupted energy metabolism due to infection. As a result of the damage caused by K. pneumoniae infection, changes occurred in the amount of non-enzymatic antioxidants, uric acid, bilirubin and albumin. Due to K. pneumoniae infection, the amount of calcium, potassium, magnesium and phosphorus altered. This study showed that G. mellonella larvae was important infection model in the investigation of infectious cell damage and physiological effects, given the opportunistic nature of the K. pneumoniae pathogen and the lack of adequate animal models.

Infective endocarditis by Klebsiella species: a systematic review.

This study aimed to systematically analyze all cases of infective endocarditis (IE) by Klebsiella species in the literature. A systematic review of PubMed, Scopus and Cochrane library (through 27th January 2021) for studies providing epidemiological, clinical, microbiological as well as treatment data and outcomes of IE by Klebsiella species was performed. In this review, a total of 66 studies were included, providing data for 67 patients. A prosthetic valve was present in 16.4%, while the most common causative pathogen was K. pneumoniae followed by K. oxytoca. The aortic valve was the most commonly infected intracardiac site, followed by the mitral valve. The diagnosis was based on transthoracic echocardiography in 46.2%, while the diagnosis was set at autopsy in 9.2% of included patients. Blood cultures were positive in 93.8%. Fever and sepsis were the most frequent clinical presentations, followed by embolic phenomena, paravalvular abscess, and heart failure. Cephalosporins, aminoglycosides, and carbapenems were the most frequently used antimicrobials. Surgical treatment along with antimicrobials was performed in 37.3% of included patients. Clinical cure was noted in 80.3%, while the overall mortality was 19.4%. Infection at the aortic valve was independently associated with mortality by IE. This systematic review gives a comprehensive description of IE by Klebsiella and provides information on epidemiology, clinical manifestations, therapeutic strategies and their outcomes.

Correlation between biofilm formation and carbapenem resistance among clinical isolates of Klebsiella pneumoniae.

BACKGROUND: Klebsiella pneumoniae is a Gram-negative enteric bacterium that causes nosocomial infections; this bacterium has survived from harsh condition using biofilm formation in hospital equipment and cause severe infection. In the other hand, the emergence and extension of carbapenem resistance burden among K. pneumonia producing biofilm is the current concern of public health services. There are controversial findings about this subject. The aim of this study was to evaluate the correlation between biofilm formation and resistance to carbapenem among clinical isolates of K. pneumoniae. METHODS: A total of 160 K. pneumoniae isolates were collected from various infections of hospitalized patients. The Carba NP test and molecular methods were used for detection of carbapenem resistance isolates of K. pneumonia. Subsequently, the ability for biofilm production was performed from all isolates. Finally, Correlation of biofilm formation among carbapenem resistant isolates was calculated using χ2 and Fisher's exact tests. RESULTS: Among K. pneumoniae isolates 42.5% have carbapenemase activity by Carba NP test, while carbapenemase genes were detected in 35.6% of isolates in amplification assay. Moreover, there are 52.5% (n= 84) of all isolates were formed a strong biofilm, while 38.1% (n= 61) and 9.3% (n= 15) of isolates were middle and weak biofilm producer, respectively. Among carbapenem resistant cases (n= 68), there are 77.9% (n= 53) and 22% (n= 15) of isolates were reported as strong and middle biofilm producer, respectively. We see a significant correlation was seen between biofilm formation ability and carbapenem resistant isolates (p-value < 0.00001). CONCLUSION: The increase of carbapenem resistance burden in biofilm producing isolates of K. pneumoniae is considered as serious alert and the basic measures to combat this phenomenon is imperative.

Monomicrobial Klebsiella pneumoniae necrotizing fasciitis: an emerging life-threatening entity.

BACKGROUND AND AIMS: Necrotizing fasciitis (NF) although rare, is a potentially fatal infection. The majority of cases are polymicrobial, although a recent surge has been reported in monomicrobial NF caused by Klebsiella pneumoniae (KP-NF). KP-NF recently accounted for an average of 16% among all pathogens, with highest mortality rate of 60%. This review discusses the important aspects of KP-NF with additional notes on the implications of multidrug resistant infections. SOURCES: The literature was searched using PubMed. Klebsiella pneumoniae isolated monomicrobially in NF cases was used as the selection criteria. CONTENT: KP-NF predominates in East Asia with the majority of cases reported from Taiwan alone. Reports from the Western hemisphere are also gradually rising. This infection has invariably presented with underlying predisposing factors occurring mostly in individuals with compromised host immunity. Diabetes, chronic liver disease, and instrumentation are important risk factors. With haematogenous spread more common, multifocal involvement via metastasis is reported. Clinical presentations are usually aggressive with rapid progression despite antimicrobial therapy. It may even present with severe sepsis. Clinicians must be aware of the differential diagnosis of such severe presentations. Emergency surgical explorations and microbiological investigations clinch the diagnosis. Outcomes are not favourable, with a high mortality rate of 40% even after appropriate interventions. Nosocomial KP-NF cases are more fulminant and multidrug resistant with even higher mortality rates (approx. 70%). IMPLICATIONS: KP-NF with its virulent course and high mortality, is an emerging life threat. Clinicians must be aware of its key features. Further comprehensive studies are needed for better insights into the spectrum of this fatal infection.

ENDOGENOUS KLEBSIELLA PNEUMONIAE ENDOPHTHALMITIS IN NORTHERN CALIFORNIA.

PURPOSE: To report the clinical features, treatment modalities, and visual outcomes in 12 eyes with endogenous Klebsiella pneumoniae endophthalmitis (EKPE). METHODS: The medical records of all patients diagnosed with EKPE at Stanford Hospital (Palo Alto, CA) and Santa Clara Valley County Hospital (Santa Clara, CA) from January 2000 to March 2017 were retrospectively reviewed. RESULTS: A total of 10 patients (12 eyes) were diagnosed with EKPE. The median age at presentation was 56, 80% were male, and 30% were non-Asian. Presenting visual acuities ranged from 20/20 to no light perception. Of the 12 eyes 10 received a tap and injection (range, 1-33 injections per eye), 2 eyes underwent primary enucleation or evisceration, and 1 patient underwent pars plana vitrectomy after tap and injection. Final visual acuities ranged from no light perception (six eyes) to 20/300 or better (five eyes). Five patients eventually underwent evisceration or enucleation. All cases were associated with positive blood and/or vitreous cultures and had concurrent systemic infection. CONCLUSION: Endogenous Klebsiella pneumoniae endophthalmitis is a rare, but devastating, ocular infection. Most cases in this series resulted in light perception vision or worse, and almost half required enucleation or evisceration. In light of the virulence of EKPE, early diagnosis and treatment should be initiated in all suspected cases.

Recurrent wheezing in neonatal pneumonia is associated with combined infection with Respiratory Syncytial Virus and Staphylococcus aureus or Klebsiella pneumoniae.

Both viral and bacterial infections can be associated with wheezing episodes in children; however, information regarding combined infections with both viral and bacterial pathogens in full term neonates is limited. We sought to investigate the effects of viral-bacterial codetection on pneumonia severity and recurrent wheezing. A retrospective cohort study was conducted on neonates admitted to our hospital with pneumonia from 2009 to 2015. Of 606 total cases, 341 were diagnosed with RSV only, and 265 were diagnosed with both RSV and a potential bacterial pathogen. The leading four species of bacteria codetected with RSV were Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Enterobacter cloacae. Neonates with RSV and a potential bacterial pathogen were significantly more likely to have worse symptoms, higher C-reactive protein values and more abnormal chest x-ray manifestations with Bonferroni correction for multiple comparisons (P < 0.01). On Cox regression analysis, an increased risk of recurrent wheezing was found for neonates positive for RSV-Staphylococcus aureus and RSV-Klebsiella pneumoniae. Our findings indicate that the combination of bacteria and RSV in the neonatal airway is associated with more serious clinical characteristics. The presence of RSV and Staphylococcus aureus or Klebsiella pneumoniae may provide predictive markers for wheeze.

Hypermucoviscous Klebsiella syndrome it's in the community!

Hypermucoviscous Klebsiella syndrome is a unique syndrome caused by a new variant of Klebsiella pneumoniae (KP), characterized by abscess formation at distant body sites. This emerging KP strain is different from the usual classic strains in having the rmp gene which increases capsule formation making this strain resistant to phagocytosis and helping in its dissemination to distant organs. A 50 years old diabetic man presented with facial swelling after dental procedure which progressively increased despite being on antibiotics. On examination he was febrile, had neck swelling with signs of inflammation and tender hepatomegaly. Ultrasonography showed submental and liver abscesses which were subsequently drained and both cultures isolated KP with hypermucoid colonies on agar plate and a positive string test indicating the presence of this new hypervirulent strain of KP. Therefore, a diagnosis of Hypermucoviscous Klebsiella syndrome should be considered in all patients who present with KP infection with multiple organ abscesses..

Propensity score matched analysis comparing the clinical outcome of Klebsiella pneumoniae and Escherichia coli causing community-onset monomicrobial bacteremia.

Bacteremia is a life-threatening condition that is associated with substantial healthcare costs. Escherichia coli and Klebsiella pneumoniae are the leading causes of community-onset gram-negative bacteremia. However, a comprehensive comparison between these pathogens involved in bacteremia episodes has yet to be reported.In this retrospective cohort study, adults with community-onset monomicrobial bacteremia caused by E coli or K pneumoniae were recruited in the emergency department of a medical center during a 6-year period, and the clinical variables were collected retrospectively from medical records. The complicated abscess occurrence was determined through imaging studies, according to the opinion of an infectious disease consultant. According to the independent predictors of 28-day mortality identified through multivariate regression analyses, patients in the E coli group were propensity score matched (PSM) in a 1:1 ratio to those in the K pneumoniae group.A total of 274 and 823 adults with K pneumoniae and E coli bacteremia were included in the present study. The K pneumoniae group had more patients with fatal comorbidities (McCabe classification), critical illness (Pitt bacteremia score ≥ 4) at bacteremia onset, and initial syndrome (e.g., severe sepsis and septic shock) as well as a higher crude mortality rate than did the E coli group. After appropriate matching, no significant differences were observed in the critical illness at bacteremia onset, initial syndrome, major comorbidities, and comorbidity severity of the 2 groups (E coli, n = 242; K pneumoniae, n = 242). Furthermore, despite similar 14- and 28-day crude mortality rates between the 2 PSM groups, more frequent abscess occurrences and a longer length of hospitalization were observed in the K pneumoniae group than in the E coli group.Conclusively, numerous clinical features at initial presentations varied between the E coli and K pneumoniae groups. Despite conducting a PSM analysis to control the differences in the baseline characteristics, a longer length of hospitalization and more frequent abscess occurrences were observed in the K pneumoniae group than in the E coli group.

Inhibition of nitric oxide production reverses diabetes-induced Kupffer cell activation and Klebsiella pneumonia liver translocation.

Klebsiella pneumoniae (KP) is the most common pathogen of pyogenic liver abscess in East and Southeast Asia and diabetes mellitus (DM) is a major risk factor. The effect and mechanism of diabetes on KP liver abscess was examined in streptozotocin-induced diabetic mice and Akita mice (C57BL/6J-Ins2Akita). KP translocation to liver and plasma alaine transaminase levels were increased and liver clearance of KP was decreased in DM mice. Diabetic mice exhibited overgrowth of Enterococcus as well as E.coli and decreased lactobacilli/bifidas growth in intestine, increased intestinal iNOS protein and nitrite levels in portal vein, and increased IL-1ß and TNF-α expression of Kupffer cells. Fructooligosaccharides (FOS) or dead L. salivarius (dLac) supplementation reversed diabetes-induced enteric dysbiosis, NO levels in portal vein, and KP translocation to liver. L-NAME treatment decreased intestinal iNOS protein expression as well as Kupffer cell activation and increased liver clearance of KP in DM mice. Dead E.coli (2×108 CFU/ml) feeding for one week induced iNOS and TLR4 expression of intestine in germ-free (GF) mice. Dead bacteria feeding induced IL-1ß and TNF-α expression of Kupffer cells in GF mice but not in GF TLR4-/- mice. In conclusion, balance of intestinal microflora is important for preventing intestinal iNOS expression, Kupffer cell activation, and KP liver translocation in diabetes. Reversal of diabetes-induced enteric dysbiosis with FOS or dead L. salivarius decreases diabetes-induced intestinal iNOS expression and KP liver translocation. Diabetes induces Kupffer cell activation and KP liver translocation through enteric dysbiosis and nitric oxide production.

More Than Meets the Eye: Klebsiella pneumoniae Invasive Liver Abscess Syndrome Presenting with Endophthalmitis.

BACKGROUND: Endophthalmitis is a feared complication of pyogenic liver abscesses caused by hypervirulent Klebsiella pneumoniae strains. First described in East Asia in the 1980s, this invasive syndrome is only recently emerging in Europe and America. CASE REPORT: We describe an 84-year-old man who presented to the emergency department with fever, orbital cellulitis, and bilateral visual loss. Although the patient had no overt abdominal symptoms, computed tomography scan revealed a pyogenic liver abscess. Blood cultures were positive for K. pneumoniae. Initial treatment consisted of intravenous ceftriaxone and intravitreal ceftazidime. A unilateral vitrectomy was performed. The patient survived with severe visual sequelae. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: K. pneumoniae pyogenic liver abscess with metastatic endophthalmitis is a relatively new syndrome that should be considered in patients presenting with acute vision loss who appear septic, with or without abdominal complaints. Early recognition prohibits delays in lifesaving treatment.

The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia.

Bacterial pneumonia is a significant healthcare burden worldwide. Failure to resolve inflammation after infection precipitates lung injury and an increase in morbidity and mortality. Gram-negative bacteria are common in pneumonia and increased levels of the mito-damage-associated molecular pattern (DAMP) cardiolipin can be detected in the lungs. Here we show that mice infected with Klebsiella pneumoniae develop lung injury with accumulation of cardiolipin. Cardiolipin inhibits resolution of inflammation by suppressing production of anti-inflammatory IL-10 by lung CD11b+Ly6GintLy6CloF4/80+ cells. Cardiolipin induces PPARγ SUMOylation, which causes recruitment of a repressive NCOR/HDAC3 complex to the IL-10 promoter, but not the TNF promoter, thereby tipping the balance towards inflammation rather than resolution. Inhibition of HDAC activity by sodium butyrate enhances recruitment of acetylated histone 3 to the IL-10 promoter and increases the concentration of IL-10 in the lungs. These findings identify a mechanism of persistent inflammation during pneumonia and indicate the potential of HDAC inhibition as a therapy.

Protective Effect of Inflammasome Activation by Hydrogen Peroxide in a Mouse Model of Septic Shock.

OBJECTIVES: To study the effect of a lack of antioxidant defenses during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice. SETTING: Laboratory experiments. SUBJECTS: C57Bl6 and glutathione peroxidase 1 knockout mice. INTERVENTION: Murine acute pneumonia model induced by Klebsiella pneumonia. MEASUREMENTS AND MAIN RESULTS: We show here that despite a lack of one of the major antioxidant defense enzymes, glutathione peroxidase 1 knockout mice are protected during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice. Furthermore, this protective effect was suppressed when antioxidant defenses were restored. Infected glutathione peroxidase 1 mice showed an early and significant, albeit transient, increase in the activity of the NOD-like receptor family, pyrin domain containing 3 inflammasome when compared with wild-type mice. The key role of the NOD-like receptor family, pyrin domain containing 3 inflammasome during acute pneumonia was confirmed in vivo when the protective effect was suppressed by treating glutathione peroxidase 1 mice with an interleukin-1 receptor antagonist. Additionally we report, in vitro, that increased concentrations of active caspase-1 and interleukin-1ß are related to an increased concentration of hydrogen peroxide in bacterially infected glutathione peroxidase 1 macrophages and that restoring hydrogen peroxide antioxidant defenses suppressed this effect. CONCLUSIONS: Our findings demonstrate that, contrary to current thinking, an early intervention targeting NOD-like receptor family, pyrin domain containing 3 inflammasome activity induces a timely and efficient activation of the innate immune response during acute infection. Our findings also demonstrate a role for hydrogen peroxide in the mechanisms tightly regulating NOD-like receptor family, pyrin domain containing 3 activation.

Impact of glycemic control on capsular polysaccharide biosynthesis and opsonophagocytosis of Klebsiella pneumoniae: Implications for invasive syndrome in patients with diabetes mellitus.

Klebsiella pneumoniae (KP), with production of abundant capsular polysaccharide (CPS), is capable of causing invasive syndrome. Environmental glucose stimuli may increase CPS biosynthesis. We aimed to investigate the relationship between glycemic control and KP-mediated invasive syndrome in diabetic patients and the effect of glucose on CPS biosynthesis. Diabetic patients with community-acquired KP bacteremia were included to study the risk factors of invasive syndrome. KP-M1, a serotype-K1 KP clinical isolate, was used to examine the CPS biosynthesis and cps gene expression, and the effect of exogenous glucose on bacterial phagocytosis and killing. We found that invasive syndrome was significantly more common in diabetic patients who were infected with strains expressing the K1 serotype (adjusted odds ratio [AOR], 8.32; 95% confidence interval [CI], 1.56-44.24; p=0.01), and had poor glycemic control (HbA1c ≥9%; AOR, 5.66; 95% CI, 2.01-15.92; p<0.01). Pre-incubation of KP-M1 in media containing different gradient glucose concentrations enhanced CPS biosynthesis and cps gene expression in high glucose (0.5%) concentration, which leads to increasing bacterial resistance to phagocytosis and killing. High glucose levels reflected by poor glycemic control may stimulate CPS biosynthesis and cps gene expression of highly virulent KP, which increase resistance to phagocytosis and contribute to development of invasive syndrome.

Hemodialysis Catheter Heat Transfer for Biofilm Prevention and Treatment.

Central line-associated bloodstream infections (CLABSIs) are not easily treated, and many catheters (e.g., hemodialysis catheters) are not easily replaced. Biofilms (the source of infection) on catheter surfaces are notoriously difficult to eradicate. We have recently demonstrated that modest elevations of temperature lead to increased staphylococcal susceptibility to vancomycin and significantly soften the biofilm matrix. In this study, using a combination of microbiological, computational, and experimental studies, we demonstrate the efficacy, feasibility, and safety of using heat as an adjuvant treatment for infected hemodialysis catheters. Specifically, we show that treating with heat in the presence of antibiotics led to additive killing of Staphylococcus epidermidis with similar trends seen for Staphylococcus aureus and Klebsiella pneumoniae. The magnitude of temperature elevation required is relatively modest (45-50°C) and similar to that used as an adjuvant to traditional cancer therapy. Using a custom-designed benchtop model of a hemodialysis catheter, positioned with tip in the human vena cava as well as computational fluid dynamic simulations, we demonstrate that these temperature elevations are likely achievable in situ with minimal increased in overall blood temperature.

FPR2/ALX activation reverses LPS-induced vascular hyporeactivity in aorta and increases survival in a pneumosepsis model.

The formylpeptide receptor 2 (FPR2/ALX) is a very promiscuous receptor, utilized by lipid and protein ligands that trigger pro- or anti-inflammatory responses. FPR2/ALX expression is increased in lung tissues of septic animals and its activation has a beneficial therapeutic effect by controlling exacerbated inflammation. Although FPR2/ALX expression was observed in vascular smooth muscle cells, its role in vascular reactivity in inflammatory conditions has not been studied. In this study, we report that LPS increases FPR2/ALX expression in vascular smooth muscle cells (A7r5 cells) and aorta tissue, and that the selective agonist WKYMVm reverses LPS-induced vascular hyporeactivity in mouse aorta rings. Mice bearing pneumosepsis by Klebsiella pneumoniae and treated with WKYMVm recovered the reactivity to vasoconstrictors and the survival improved by 40%. As for the mechanisms involved, FPR2/ALX activation decreases NO production in LPS-stimulated cells and aorta, but it does not seem involve the regulation of NOS-2 expression. The molecular mechanism by which the peptide inhibits NO production still needs to be elucidated, but our data suggests an important role for NO in the WKYMVm beneficial effect observed in LPS injury and sepsis. In conclusion, our data suggest, for the first time, that a receptor, primarily described as a mediator of immune responses, may have an important role in the vascular dysfunctions observed in sepsis and may be a possible target for new therapeutic interventions.