The Role of ZntA in Klebsiella pneumoniae Zinc Homeostasis

Klebsiella pneumoniae is a leading cause of healthcare-associated infections, including pneumonia, urinary tract infections, and sepsis. Treatment of K. pneumoniae infections is becoming increasingly challenging due to high levels of antibiotic resistance and the rising prevalence of carbapenem-resistant, extended-spectrum β-lactamases producing strains.

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Carbapenem-Resistant Klebsiella pneumoniae Urinary Tract Infection following Solid Organ Transplantation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04284-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 553-557 ◽

Cited By ~ 30

Author(s):

Kyle D. Brizendine ◽

Sandra S. Richter ◽

Eric D. Cober ◽

David van Duin

Keyword(s):

Urinary Tract ◽

Klebsiella Pneumoniae ◽

Solid Organ Transplantation ◽

Organ Transplant ◽

Carbapenem Resistance ◽

First Episode ◽

Solid Organ ◽

Content Type ◽

Carbapenem Resistant ◽

Tract Infections

ABSTRACTCarbapenem-resistantKlebsiella pneumoniae(CRKP) is an emerging pathogen with a devastating impact on organ transplant recipients (OTRs). Data describing urinary tract infections (UTIs) due to CRKP, compared to extended-spectrum β-lactamase (ESBL)-producing and susceptibleK. pneumoniae, are lacking. We conducted a retrospective cohort study comparing OTRs with a first episode of UTI due to CRKP, ESBL-producingK. pneumoniae, or susceptibleK. pneumoniae. We identified 108 individuals; 22 (20%) had UTIs due to CRKP, 22 (20%) due to ESBL-producingK. pneumoniae, and 64 (60%) due to susceptibleK. pneumoniae. Compared to susceptibleK. pneumoniae(27%), patients with UTIs due to CRKP or ESBL-producingK. pneumoniaewere more likely to have a ≥24-hour stay in the intensive care unit (ICU) before or after development of the UTI (64% and 77%, respectively;P< 0.001). Among 105/108 hospitalized patients (97%), the median lengths of stay prior to UTI with CRKP or ESBL-producingK. pneumoniae(7 and 8 days, respectively) were significantly longer than that for susceptibleK. pneumoniae(1 day;P< 0.001). Clinical failure was observed for 8 patients (36%) with CRKP, 4 (18%) with ESBL-producingK. pneumoniae, and 9 (14%) with susceptibleK. pneumoniae(P= 0.073). Microbiological failure was seen for 10 patients (45%) with CRKP, compared with 2 (9%) with ESBL-producingK. pneumoniaeand 2 (3%) with susceptibleK. pneumoniae(P< 0.001). In multivariable logistic regression analyses, CRKP was associated with greater odds of microbiological failure (versus ESBL-producingK. pneumoniae: odds ratio [OR], 9.36, 95% confidence interval [CI], 1.94 to 72.1; versus susceptibleK. pneumoniae: OR, 31.4, 95% CI, 5.91 to 264). In conclusion, CRKP is associated with ICU admission, long length of stay, and microbiological failure among OTRs with UTIs. Greater numbers are needed to determine risk factors for infection and differences in meaningful endpoints associated with carbapenem resistance.

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A Serendipitous Mutation Reveals the Severe Virulence Defect of a Klebsiella pneumoniae fepB Mutant

mSphere ◽

10.1128/msphere.00341-17 ◽

2017 ◽

Vol 2 (4) ◽

Cited By ~ 12

Author(s):

Michelle Palacios ◽

Christopher A. Broberg ◽

Kimberly A. Walker ◽

Virginia L. Miller

Keyword(s):

Antibiotic Resistance ◽

Urinary Tract ◽

Klebsiella Pneumoniae ◽

Drug Targets ◽

Carbapenem Resistance ◽

Content Type ◽

Hospital Acquired Infections ◽

Tract Infections ◽

Hospital Acquired ◽

Rapid Emergence

ABSTRACT In addition to having a reputation as the causative agent of several types of hospital-acquired infections, Klebsiella pneumoniae has gained widespread attention as a pathogen with a propensity for acquiring antibiotic resistance. It is capable of causing a range of infections, including urinary tract infections, pneumonia, and sepsis. Because of the rapid emergence of carbapenem resistance among Klebsiella strains, there is a dire need for a better understanding of virulence mechanisms and identification of new drug targets. Here, we identify the periplasmic transporter FepB as one such potential target. Klebsiella pneumoniae is considered a significant public health threat because of the emergence of multidrug-resistant strains and the challenge associated with treating life-threatening infections. Capsule, siderophores, and adhesins have been implicated as virulence determinants of K. pneumoniae, yet we lack a clear understanding of how this pathogen causes disease. In a previous screen for virulence genes, we identified a potential new virulence locus and constructed a mutant (smr) with this locus deleted. In this study, we characterize the smr mutant and show that this mutation renders K. pneumoniae avirulent in a pneumonia model of infection. The smr mutant was expected to have a deletion of three genes, but subsequent genome sequencing indicated that a much larger deletion had occurred. Further analysis of the deleted region indicated that the virulence defect of the smr mutant could be attributed to the loss of FepB, a periplasmic protein required for import of the siderophore enterobactin. Interestingly, a ΔfepB mutant was more attenuated than a mutant unable to synthesize enterobactin, suggesting that additional processes are affected. As FepB is highly conserved among the members of the family Enterobacteriaceae, therapeutic targeting of FepB may be useful for the treatment of Klebsiella and other bacterial infections. IMPORTANCE In addition to having a reputation as the causative agent of several types of hospital-acquired infections, Klebsiella pneumoniae has gained widespread attention as a pathogen with a propensity for acquiring antibiotic resistance. It is capable of causing a range of infections, including urinary tract infections, pneumonia, and sepsis. Because of the rapid emergence of carbapenem resistance among Klebsiella strains, there is a dire need for a better understanding of virulence mechanisms and identification of new drug targets. Here, we identify the periplasmic transporter FepB as one such potential target.

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Role of Klebsiella pneumoniae Type 1 and Type 3 Fimbriae in Colonizing Silicone Tubes Implanted into the Bladders of Mice as a Model of Catheter-Associated Urinary Tract Infections

Infection and Immunity ◽

10.1128/iai.00348-13 ◽

2013 ◽

Vol 81 (8) ◽

pp. 3009-3017 ◽

Cited By ~ 57

Author(s):

Caitlin N. Murphy ◽

Martin S. Mortensen ◽

Karen A. Krogfelt ◽

Steven Clegg

Keyword(s):

Urinary Tract ◽

Klebsiella Pneumoniae ◽

Urinary Tract Infections ◽

Wild Type ◽

Content Type ◽

Tract Infections ◽

Type 3

ABSTRACTCatheter-associated urinary tract infections are biofilm-mediated infections that cause a significant economic and health burden in nosocomial environments. Using a newly developed murine model of this type of infection, we investigated the role of fimbriae in implant-associated urinary tract infections by the Gram-negative bacteriumKlebsiella pneumoniae, which is a proficient biofilm former and a commonly isolated nosocomial pathogen. Studies have shown that type 1 and type 3 fimbriae are involved in attachment and biofilm formationin vitro, and these fimbrial types are suspected to be important virulence factors during infection. To test this hypothesis, the virulence of fimbrial mutants was assessed in independent challenges in which mouse bladders were inoculated with the wild type or a fimbrial mutant and in coinfection studies in which the wild type and fimbrial mutants were inoculated together to assess the results of a direct competition in the urinary tract. Using these experiments, we were able to show that both fimbrial types serve to enhance colonization and persistence. Additionally, a double mutant had an additive colonization defect under some conditions, indicating that both fimbrial types have unique roles in the attachment and persistence in the bladder and on the implant itself. All of these mutants were outcompeted by the wild type in coinfection experiments. Using these methods, we are able to show that type 1 and type 3 fimbriae are important colonization factors in the murine urinary tract when an implanted silicone tube is present.

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Ertapenem-Containing Double-Carbapenem Therapy for Treatment of Infections Caused by Carbapenem-Resistant Klebsiella pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01569-15 ◽

2015 ◽

Vol 60 (1) ◽

pp. 669-673 ◽

Cited By ~ 33

Author(s):

Jessica B. Cprek ◽

Jason C. Gallagher

Keyword(s):

Urinary Tract ◽

Klebsiella Pneumoniae ◽

Clinical Success ◽

Treatment Options ◽

Bloodstream Infections ◽

Content Type ◽

Skin Structure ◽

Carbapenem Resistant ◽

Tract Infections ◽

Intraabdominal Infections

ABSTRACTWe describe outcomes of patients with infections with carbapenem-resistantKlebsiella pneumoniae(CRKP) who received ertapenem-containing double-carbapenem therapy (ECDCT). Clinical success was observed in 7/18 (39%) patients overall: bloodstream infections, 3/7 (43%); pneumonia, 1/5 (20%); intraabdominal infections, 0/2 (0%); urinary tract infections, 2/3 (67%); and a skin and skin structure infection, 1/1 (100%). Microbiologic success was observed in 11/14 (79%) evaluable patients; 5/18 (28%) patients died. ECDCT may be effective for CRKP infections with limited treatment options.

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Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-ResistantKlebsiella pneumoniaeStrains Identifies Genes for Antibiotic Resistance and Virulence

mSystems ◽

10.1128/msystems.00202-19 ◽

2019 ◽

Vol 4 (4) ◽

Cited By ~ 5

Author(s):

Muyoung Lee ◽

Naina Adren Pinto ◽

Chan Yeong Kim ◽

Sunmo Yang ◽

Roshan D’Souza ◽

...

Keyword(s):

Antibiotic Resistance ◽

Klebsiella Pneumoniae ◽

Carbapenem Resistance ◽

Clinical Isolates ◽

Functional Modules ◽

Antibiotic Resistant ◽

Content Type ◽

Functional Association ◽

Carbapenem Resistant ◽

Tract Infections

ABSTRACTGlobal increases in the use of carbapenems have resulted in several strains of Gram-negative bacteria acquiring carbapenem resistance, thereby limiting treatment options.Klebsiella pneumoniaeis a common carbapenem-resistant pathogenic bacterium that is widely studied to identify novel antibiotic resistance mechanisms and drug targets. Antibiotic-resistant clinical isolates generally harbor many genetic alterations, and the identification of responsible mutations would provide insights into the molecular mechanisms of antibiotic resistance. We propose a method to prioritize mutated genes responsible for antibiotic resistance on the basis of expression changes in their local subnetworks, hypothesizing that mutated genes that show significant expression changes among the corresponding functionally associated genes are more likely to be involved in the carbapenem resistance. For network-based gene prioritization, we developed KlebNet (www.inetbio.org/klebnet), a genome-scale cofunctional network ofK. pneumoniaegenes. Using KlebNet, we reconstructed the functional modules for carbapenem resistance and virulence and identified the functional association between antibiotic resistance and virulence. Using complementation assays with the top candidate genes, we were able to validate a novel gene that negatively regulated carbapenem resistance and four novel genes that positively regulated virulence inGalleria mellonellalarvae. Therefore, our study demonstrated the feasibility of network-based identification of genes required for antibiotic resistance and virulence of human-pathogenic bacteria.IMPORTANCEKlebsiella pneumoniaeis a major bacterial pathogen that causes pneumonia and urinary tract infections in human.K. pneumoniaeinfections are treated with carbapenem, but carbapenem-resistantK. pneumoniaehas been spreading worldwide. We are able to identify antimicrobial-resistant genes among mutated genes of the antibiotic-resistant clinical isolates. However, they usually harbor many mutated genes, including those that cause weak or neutral functional effects. Therefore, we need to prioritize the mutated genes to identify the more likely candidates for the follow-up functional analysis. For this study, we present a functional network ofK. pneumoniaegenes and propose a network-based method of prioritizing the mutated genes of the resistant clinical isolates. We also reconstructed the network-based functional modules for carbapenem resistance and virulence and retrieved the functional association between antibiotic resistance and virulence. This study demonstrated the feasibility of network-based analysis of clinical genomics data for the study ofK. pneumoniaeinfection.

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Activity of Meropenem-Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in a Murine Model of Pyelonephritis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01439-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 9

Author(s):

William J. Weiss ◽

Mark E. Pulse ◽

Phung Nguyen ◽

Kelly Peterson ◽

Jessica Silva ◽

...

Keyword(s):

Urinary Tract ◽

Klebsiella Pneumoniae ◽

Urinary Tract Infections ◽

Bacterial Killing ◽

Gram Negative ◽

Content Type ◽

Highly Active ◽

Carbapenem Resistant ◽

Tract Infections ◽

Carbapenem Resistant Enterobacteriaceae

ABSTRACT The recently approved combination of meropenem and vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae. We evaluated the efficacy of meropenem-vaborbactam against three clinically relevant isolates in a murine pyelonephritis model. The data indicate that the combination of meropenem and vaborbactam significantly increased bacterial killing compared to that with the untreated controls. These data suggest that this combination may have utility in the treatment of complicated urinary tract infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.

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Epidemiology and antimicrobial resistance of Acinetobacter

International Journal of Antibiotics and Probiotics ◽

10.31405/ijap.4-5.18.05 ◽

2018 ◽

Vol 2 (4) ◽

pp. 46-59

Author(s):

A.G. Salmanov ◽

O.M. Verner ◽

L.F. Slepova

Keyword(s):

Antibiotic Resistance ◽

Laboratory Testing ◽

Immunocompromised Host ◽

Clinical Problem ◽

Healthcare Associated Infections ◽

Opportunistic Bacteria ◽

Acinetobacter Spp ◽

Healthcare Associated ◽

Major Clinical Problem

Species of the Acinetobacter represent opportunistic bacteria with a growing clinical significance for Healthcare-associated infections (HAIs). In this literature review, we focus on the current role of Acinetobacter in infectious pathology and describe taxonomy, pathogenicity, and antibiotic resistance of these bacteria. Pathogenesis and regulation of virulence factors in Acinetobacter spp. are described in detail. The majority of acinetobacterial infections are associated with A. baumannii and occur predominantly in an immunocompromised host. Usually, acinetobacterial infections are characterized by local purulent inflammation; in severe cases, meningitis and sepsis may develop. Antibiotic resistance of Acinetobacter is a major clinical problem; therefore we give special attention to laboratory testing of resistance to antibiotics as well as identification of Acinetobacter.

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Costs of ambulatory pediatric healthcare-associated infections: Central-line–associated bloodstream infection (CLABSIs), catheter-associated urinary tract infection (CAUTIs), and surgical site infections (SSIs)

Infection Control and Hospital Epidemiology ◽

10.1017/ice.2020.305 ◽

2020 ◽

Vol 41 (11) ◽

pp. 1292-1297

Author(s):

Michael L. Rinke ◽

Suzette O. Oyeku ◽

William J. H. Ford ◽

Moonseong Heo ◽

Lisa Saiman ◽

...

Keyword(s):

Urinary Tract ◽

Ambulatory Surgery ◽

Bloodstream Infections ◽

Surgical Site Infections ◽

Central Line ◽

Healthcare Associated Infections ◽

Retrospective Case ◽

Additional Costs ◽

Tract Infections ◽

Healthcare Associated

AbstractObjective:Ambulatory healthcare-associated infections (HAIs) occur frequently in children and are associated with morbidity. Less is known about ambulatory HAI costs. This study estimated additional costs associated with pediatric ambulatory central-line–associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTI), and surgical site infections (SSIs) following ambulatory surgery.Design:Retrospective case-control study.Setting:Four academic medical centers.Patients:Children aged 0–22 years seen between 2010 and 2015 and at risk for HAI as identified by electronic queries.Methods:Chart review adjudicated HAIs. Charges were obtained for patients with HAIs and matched controls 30 days before HAI, on the day of, and 30 days after HAI. Charges were converted to costs and 2015 USD. Mixed-effects linear regression was used to estimate the difference-in-differences of HAI case versus control costs in 2 models: unrecorded charge values considered missing and a sensitivity analysis with unrecorded charge considered $0.Results:Our search identified 177 patients with ambulatory CLABSIs, 53 with ambulatory CAUTIs, and 26 with SSIs following ambulatory surgery who were matched with 382, 110, and 75 controls, respectively. Additional cost associated with an ambulatory CLABSI was $5,684 (95% confidence interval [CI], $1,005–$10,362) and $6,502 (95% CI, $2,261–$10,744) in the 2 models; cost associated with a CAUTI was $6,660 (95% CI, $1,055, $12,145) and $2,661 (95% CI, −$431 to $5,753); cost associated with an SSI following ambulatory surgery at 1 institution only was $6,370 (95% CI, $4,022–$8,719).Conclusions:Ambulatory HAI in pediatric patients are associated with significant additional costs. Further work is needed to reduce ambulatory HAIs.

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Role of age and sex in determining antibiotic resistance in febrile urinary tract infections

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2016.08.015 ◽

2016 ◽

Vol 51 ◽

pp. 89-96 ◽

Cited By ~ 6

Author(s):

Dong Sup Lee ◽

Hyun-Sop Choe ◽

Hee Youn Kim ◽

Je Mo Yoo ◽

Woong Jin Bae ◽

...

Keyword(s):

Antibiotic Resistance ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Febrile Urinary Tract Infections ◽

Tract Infections ◽

Age And Sex

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Comparative Effectiveness of Aminoglycosides, Polymyxin B, and Tigecycline for Clearance of Carbapenem-Resistant Klebsiella pneumoniae from Urine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00387-11 ◽

2011 ◽

Vol 55 (12) ◽

pp. 5893-5899 ◽

Cited By ~ 79

Author(s):

Michael J. Satlin ◽

Christine J. Kubin ◽

Jill S. Blumenthal ◽

Andrew B. Cohen ◽

E. Yoko Furuya ◽

...

Keyword(s):

New York ◽

Klebsiella Pneumoniae ◽

Urine Culture ◽

Active Agent ◽

Polymyxin B ◽

Content Type ◽

Carbapenem Resistant ◽

Tract Infections

ABSTRACTCarbapenem-resistantKlebsiella pneumoniae(CRKP) is an increasingly common cause of health care-associated urinary tract infections. Antimicrobials within vitroactivity against CRKP are typically limited to polymyxins, tigecycline, and often, aminoglycosides. We conducted a retrospective cohort study of cases of CRKP bacteriuria at New York-Presbyterian Hospital from January 2005 through June 2010 to compare microbiologic clearance rates based on the use of polymyxin B, tigecycline, or an aminoglycoside. We constructed three active antimicrobial cohorts based on the active agent used and an untreated cohort of cases that did not receive antimicrobial therapy with Gram-negative activity. Microbiologic clearance was defined as having a follow-up urine culture that did not yield CRKP. Cases without an appropriate follow-up culture or that received multiple active agents or less than 3 days of the active agent were excluded. Eighty-seven cases were included in the active antimicrobial cohorts, and 69 were included in the untreated cohort. The microbiologic clearance rate was 88% in the aminoglycoside cohort (n= 41), compared to 64% in the polymyxin B (P= 0.02;n= 25), 43% in the tigecycline (P< 0.001;n= 21), and 36% in the untreated (P< 0.001;n= 69) cohorts. Using multivariate analysis, the odds of clearance were lower for the polymyxin B (odds ratio [OR], 0.10;P= 0.003), tigecycline (OR, 0.08;P= 0.001), and untreated (OR, 0.14;P= 0.003) cohorts than for the aminoglycoside cohort. Treatment with an aminoglycoside, when activein vitro, was associated with a significantly higher rate of microbiologic clearance of CRKP bacteriuria than treatment with either polymyxin B or tigecycline.

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