A Rare Opportunist, Morganella morganii, Decreases Severity of Polymicrobial Catheter-Associated Urinary Tract Infection

ABSTRACT Catheter-associated urinary tract infections (CAUTIs) are common hospital-acquired infections and frequently polymicrobial, which complicates effective treatment. However, few studies experimentally address the consequences of polymicrobial interactions within the urinary tract, and the clinical significance of polymicrobial bacteriuria is not fully understood. Proteus mirabilis is one of the most common causes of monomicrobial and polymicrobial CAUTI and frequently cocolonizes with Enterococcus faecalis, Escherichia coli, Providencia stuartii, and Morganella morganii. P. mirabilis infections are particularly challenging due to its potent urease enzyme, which facilitates formation of struvite crystals, catheter encrustation, blockage, and formation of urinary stones. We previously determined that interactions between P. mirabilis and other uropathogens can enhance P. mirabilis urease activity, resulting in greater disease severity during experimental polymicrobial infection. Our present work reveals that M. morganii acts on P. mirabilis in a contact-independent manner to decrease urease activity. Furthermore, M. morganii actively prevents urease enhancement by E. faecalis, P. stuartii, and E. coli. Importantly, these interactions translate to modulation of disease severity during experimental CAUTI, predominantly through a urease-dependent mechanism. Thus, products secreted by multiple bacterial species in the milieu of the catheterized urinary tract can directly impact prognosis.

Download Full-text

A rare opportunist, Morganella morganii, decreases severity of polymicrobial catheter-associated urinary tract infection

10.1101/754135 ◽

2019 ◽

Author(s):

Brian S. Learman ◽

Aimee L. Brauer ◽

Kathryn A. Eaton ◽

Chelsie E. Armbruster

Keyword(s):

Urinary Tract ◽

Disease Severity ◽

Urease Activity ◽

Bacterial Species ◽

Urinary Stones ◽

Morganella Morganii ◽

Independent Manner ◽

Urease Enzyme ◽

Providencia Stuartii ◽

Tract Infections

AbstractCatheter-associated urinary tract infections (CAUTIs) are common hospital-acquired infections and frequently polymicrobial, which complicates effective treatment. However, few studies experimentally address the consequences of polymicrobial interactions within the urinary tract, and the clinical significance of polymicrobial bacteriuria is not fully understood. Proteus mirabilis is one of the most common causes of monomicrobial and polymicrobial CAUTI, and frequently co-colonizes with Enterococcus faecalis, Escherichia coli, Providencia stuartii, and Morganella morganii. P. mirabilis infections are particularly challenging due to its potent urease enzyme, which facilitates formations of struvite crystals, catheter encrustation, blockage, and formation of urinary stones. We previously determined that interactions between P. mirabilis and other uropathogens can enhance P. mirabilis urease activity, resulting in greater disease severity during experimental polymicrobial infection. Our present work reveals that M. morganii acts on P. mirabilis in a contact-independent manner to decrease urease activity. Furthermore, M. morganii actively prevents urease enhancement by E. faecalis, P. stuartii, and E. coli. Importantly, these interactions translate to modulation of disease severity during experimental CAUTI, predominantly through a urease-dependent mechanism. Thus, products secreted by multiple bacterial species in the milieu of the catheterized urinary tract can directly impact prognosis.

Download Full-text

The Pathogenic Potential of Proteus mirabilis Is Enhanced by Other Uropathogens during Polymicrobial Urinary Tract Infection

Infection and Immunity ◽

10.1128/iai.00808-16 ◽

2016 ◽

Vol 85 (2) ◽

Cited By ~ 36

Author(s):

Chelsie E. Armbruster ◽

Sara N. Smith ◽

Alexandra O. Johnson ◽

Valerie DeOrnellas ◽

Kathryn A. Eaton ◽

...

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Disease Severity ◽

Proteus Mirabilis ◽

Tissue Damage ◽

Urease Activity ◽

Pathogenic Potential ◽

Content Type

ABSTRACT Urinary catheter use is prevalent in health care settings, and polymicrobial colonization by urease-positive organisms, such as Proteus mirabilis and Providencia stuartii, commonly occurs with long-term catheterization. We previously demonstrated that coinfection with P. mirabilis and P. stuartii increased overall urease activity in vitro and disease severity in a model of urinary tract infection (UTI). In this study, we expanded these findings to a murine model of catheter-associated UTI (CAUTI), delineated the contribution of enhanced urease activity to coinfection pathogenesis, and screened for enhanced urease activity with other common CAUTI pathogens. In the UTI model, mice coinfected with the two species exhibited higher urine pH values, urolithiasis, bacteremia, and more pronounced tissue damage and inflammation compared to the findings for mice infected with a single species, despite having a similar bacterial burden within the urinary tract. The presence of P. stuartii, regardless of urease production by this organism, was sufficient to enhance P. mirabilis urease activity and increase disease severity, and enhanced urease activity was the predominant factor driving tissue damage and the dissemination of both organisms to the bloodstream during coinfection. These findings were largely recapitulated in the CAUTI model. Other uropathogens also enhanced P. mirabilis urease activity in vitro, including recent clinical isolates of Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, and Pseudomonas aeruginosa. We therefore conclude that the underlying mechanism of enhanced urease activity may represent a widespread target for limiting the detrimental consequences of polymicrobial catheter colonization, particularly by P. mirabilis and other urease-positive bacteria.

Download Full-text

Urine Cytokine and Chemokine Levels Predict Urinary Tract Infection Severity Independent of Uropathogen, Urine Bacterial Burden, Host Genetics, and Host Age

Infection and Immunity ◽

10.1128/iai.00327-18 ◽

2018 ◽

Vol 86 (9) ◽

Cited By ~ 4

Author(s):

Chelsie E. Armbruster ◽

Sara N. Smith ◽

Lona Mody ◽

Harry L. T. Mobley

Keyword(s):

Immune Response ◽

Clinical Practice ◽

Urinary Tract ◽

Disease Severity ◽

Mouse Strain ◽

Bacterial Species ◽

Severe Disease ◽

Age Groups ◽

Bacterial Burden ◽

Content Type

ABSTRACT Urinary tract infections (UTIs) are among the most common infections worldwide. Diagnosing UTIs in older adults poses a significant challenge as asymptomatic colonization is common. Identification of a noninvasive profile that predicts likelihood of progressing from urine colonization to severe disease would provide a significant advantage in clinical practice. We monitored colonization susceptibility, disease severity, and immune response to two uropathogens in two mouse strains across three age groups to identify predictors of infection outcome. Proteus mirabilis caused more severe disease than Escherichia coli, regardless of mouse strain or age, and was associated with differences in interleukin-1β (IL-1β), beta interferon (IFN-β), CXCL5 (LIX), CCL5 (RANTES), and CCL2 (MCP-1). In a comparison of responses to infection across age groups, mature adult mice were better able to control colonization and prevent progression to kidney colonization and bacteremia than young or aged mice, regardless of mouse strain or bacterial species, and this was associated with differences in IL-23, CXCL1, and CCL5. A bimodal distribution was noted for urine colonization, which was strongly associated with bladder CFU counts and the magnitude of the immune response but independent of age or disease severity. To determine the value of urine cytokine and chemokine levels for predicting severe disease, all infection data sets were combined and subjected to a series of logistic regressions. A multivariate model incorporating IL-1β, CXCL1, and CCL2 had strong predictive value for identifying mice that did not develop kidney colonization or bacteremia, regardless of mouse genetic background, age, infecting bacterial species, or urine bacterial burden. In conclusion, urine cytokine profiles could potentially serve as a noninvasive decision support tool in clinical practice and contribute to antimicrobial stewardship.

Download Full-text

Dynamics of Resistance Plasmids in Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae during Postinfection Colonization

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02201-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 5

Author(s):

Alma Brolund ◽

Fredrika Rajer ◽

Christian G. Giske ◽

Öjar Melefors ◽

Emilia Titelman ◽

...

Keyword(s):

Urinary Tract ◽

Gut Microbiota ◽

Temporal Dynamics ◽

Bacterial Species ◽

Genetic Material ◽

Bloodstream Infections ◽

Complex Situation ◽

Content Type ◽

Extended Spectrum ◽

Tract Infections

ABSTRACT Extended-spectrum β-lactamase-producing Enterobacteriaceae (EPE) are a major cause of bloodstream infections, and the colonization rate of EPE in the gut microbiota of individuals lacking prior hospitalization or comorbidities is increasing. In this study, we performed an in-depth investigation of the temporal dynamics of EPE and their plasmids during one year by collecting fecal samples from three patients initially seeking medical care for urinary tract infections. In two of the patients, the same strain that caused the urinary tract infection (UTI) was found at all consecutive samplings from the gut microbiota, and no other EPEs were detected, while in the third patient the UTI strain was only found in the initial UTI sample. Instead, this patient presented a complex situation where a mixed microbiota of different EPE strain types, including three different E. coli ST131 variants, as well as different bacterial species, was identified over the course of the study. Different plasmid dynamics were displayed in each of the patients, including the spread of plasmids between different strain types over time and the transposition of blaCTX-M-15 from the chromosome to a plasmid, followed by subsequent loss through homologous recombination. Small cryptic plasmids were found in all isolates from all patients, and they appear to move frequently between different strains in the microbiota. In conclusion, we could demonstrate an extensive variation of EPE strain types, plasmid composition, rearrangements, and horizontal gene transfer of genetic material illustrating the high dynamics nature and interactive environment of the gut microbiota during post-UTI carriage.

Download Full-text

Single Clinical Isolates from Acute Uncomplicated Urinary Tract Infections Are Representative of Dominant In Situ Populations

mBio ◽

10.1128/mbio.01064-13 ◽

2014 ◽

Vol 5 (2) ◽

Cited By ~ 18

Author(s):

Dana Willner ◽

Serene Low ◽

Jason A. Steen ◽

Narelle George ◽

Graeme R. Nimmo ◽

...

Keyword(s):

Escherichia Coli ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Clinical Isolates ◽

Content Type ◽

E Coli ◽

Strain Diversity ◽

Amplicon Pyrosequencing ◽

Culture Independent ◽

Tract Infections

ABSTRACTUrinary tract infections (UTIs) are one of the most commonly acquired bacterial infections in humans, and uropathogenicEscherichia colistrains are responsible for over 80% of all cases. The standard method for identification of uropathogens in clinical laboratories is cultivation, primarily using solid growth media under aerobic conditions, coupled with morphological and biochemical tests of typically a single isolate colony. However, these methods detect only culturable microorganisms, and characterization is phenotypic in nature. Here, we explored the genotypic identity of communities in acute uncomplicated UTIs from 50 individuals by using culture-independent amplicon pyrosequencing and whole-genome and metagenomic shotgun sequencing. Genus-level characterization of the UTI communities was achieved using the 16S rRNA gene (V8 region). Overall UTI community richness was very low in comparison to other human microbiomes. We strain-typedEscherichia-dominated UTIs using amplicon pyrosequencing of the fimbrial adhesin gene,fimH. There were nine highly abundantfimHtypes, and each UTI sample was dominated by a single type. Molecular analysis of the corresponding clinical isolates revealed that in the majority of cases the isolate was representative of the dominant taxon in the community at both the genus and the strain level. Shotgun sequencing was performed on a subset of eightE. coliurine UTI and isolate pairs. The majority of UTI microbial metagenomic sequences mapped to isolate genomes, confirming the results obtained using phylogenetic markers. We conclude that for the majority of acute uncomplicatedE. coli-mediated UTIs, single cultured isolates are diagnostic of the infection.IMPORTANCEIn clinical practice, the diagnosis and treatment of acute uncomplicated urinary tract infection (UTI) are based on analysis of a single bacterial isolate cultured from urine, and it is assumed that this isolate represents the dominant UTI pathogen. However, these methods detect only culturable bacteria, and the existence of multiple pathogens as well as strain diversity within a single infection is not examined. Here, we explored bacteria present in acute uncomplicated UTIs using culture-independent sequence-based methods.Escherichia coliwas the most common organism identified, and analysis ofE. colidominant UTI samples and their paired clinical isolates revealed that in the majority of infections the cultured isolate was representative of the dominant taxon at both the genus and the strain level. Our data demonstrate that in most cases single cultured isolates are diagnostic of UTI and are consistent with the notion of bottlenecks that limit strain diversity during UTI pathogenesis.

Download Full-text

New Aspects of RpoE in Uropathogenic Proteus mirabilis

Infection and Immunity ◽

10.1128/iai.02232-14 ◽

2014 ◽

Vol 83 (3) ◽

pp. 966-977 ◽

Cited By ~ 10

Author(s):

Ming-Che Liu ◽

Kuan-Ting Kuo ◽

Hsiung-Fei Chien ◽

Yi-Lin Tsai ◽

Shwu-Jen Liaw

Keyword(s):

Urinary Tract ◽

Virulence Factors ◽

Stress Responses ◽

Proteus Mirabilis ◽

Immune Cell ◽

Polymyxin B ◽

Urothelial Cells ◽

Cationic Antimicrobial Peptide ◽

Content Type ◽

Tract Infections

Proteus mirabilisis a common human pathogen causing recurrent or persistent urinary tract infections (UTIs). The underlying mechanisms forP. mirabilisto establish UTIs are not fully elucidated. In this study, we showed that loss of the sigma factor E (RpoE), mediating extracytoplasmic stress responses, decreased fimbria expression, survival in macrophages, cell invasion, and colonization in mice but increased the interleukin-8 (IL-8) expression of urothelial cells and swarming motility. This is the first study to demonstrate that RpoE modulated expression of MR/P fimbriae by regulatingmrpI, a gene encoding a recombinase controlling the orientation of MR/P fimbria promoter. By real-time reverse transcription-PCR, we found that the IL-8 mRNA amount of urothelial cells was induced significantly by lipopolysaccharides extracted fromrpoEmutant but not from the wild type. These RpoE-associated virulence factors should be coordinately expressed to enhance the fitness ofP. mirabilisin the host, including the avoidance of immune attacks. Accordingly,rpoEmutant-infected mice displayed more immune cell infiltration in bladders and kidneys during early stages of infection, and therpoEmutant had a dramatically impaired ability of colonization. Moreover, it is noteworthy that urea (the major component in urine) and polymyxin B (a cationic antimicrobial peptide) can induce expression ofrpoEby the reporter assay, suggesting that RpoE might be activated in the urinary tract. Altogether, our results indicate that RpoE is important in sensing environmental cues of the urinary tract and subsequently triggering the expression of virulence factors, which are associated with the fitness ofP. mirabilis, to build up a UTI.

Download Full-text

Global Fluoroquinolone Resistance Epidemiology and Implictions for Clinical Use

Interdisciplinary Perspectives on Infectious Diseases ◽

10.1155/2012/976273 ◽

2012 ◽

Vol 2012 ◽

pp. 1-37 ◽

Cited By ~ 148

Author(s):

Axel Dalhoff

Keyword(s):

Urinary Tract ◽

Rural Areas ◽

Methicillin Resistance ◽

Bacterial Species ◽

Fluoroquinolone Resistance ◽

Sexually Transmitted ◽

Tract Infections ◽

Almost All ◽

Healthcare Associated ◽

Resistance Rates

This paper on the fluoroquinolone resistance epidemiology stratifies the data according to the different prescription patterns by either primary or tertiary caregivers and by indication. Global surveillance studies demonstrate that fluoroquinolone resistance rates increased in the past years in almost all bacterial species exceptS. pneumoniaeandH. influenzae, causing community-acquired respiratory tract infections. However, 10 to 30% of these isolates harbored first-step mutations conferring low level fluoroquinolone resistance. Fluoroquinolone resistance increased in Enterobacteriaceae causing community acquired or healthcare associated urinary tract infections and intraabdominal infections, exceeding 50% in some parts of the world, particularly in Asia. One to two-thirds of Enterobacteriaceae producing extended spectrum -lactamases were fluoroquinolone resistant too. Furthermore, fluoroquinolones select for methicillin resistance inStaphylococci.Neisseria gonorrhoeaeacquired fluoroquinolone resistance rapidly; actual resistance rates are highly variable and can be as high as almost 100%, particularly in Asia, whereas resistance rates in Europe and North America range from <10% in rural areas to >30% in established sexual networks. In general, the continued increase in fluoroquinolone resistance affects patient management and necessitates changes in some guidelines, for example, treatment of urinary tract, intra-abdominal, skin and skin structure infections, and traveller’s diarrhea, or even precludes the use in indications like sexually transmitted diseases and enteric fever.

Download Full-text

Synchrotron X-Ray Fluorescence Microscopy of Gallium in Bladder Tissue following Gallium Maltolate Administration during Urinary Tract Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00616-13 ◽

2013 ◽

Vol 57 (11) ◽

pp. 5197-5201 ◽

Cited By ~ 3

Author(s):

Katherine R. Ball ◽

Francesca Sampieri ◽

Manuel Chirino ◽

Don L. Hamilton ◽

Robert I. R. Blyth ◽

...

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Transitional Epithelium ◽

Bladder Tissue ◽

Content Type ◽

X Ray ◽

E Coli ◽

Tract Infections ◽

X Ray Absorption

ABSTRACTA mouse model of cystitis caused by uropathogenicEscherichia coliwas used to study the distribution of gallium in bladder tissue following oral administration of gallium maltolate during urinary tract infection. The median concentration of gallium in homogenized bladder tissue from infected mice was 1.93 μg/g after daily administration of gallium maltolate for 5 days. Synchrotron X-ray fluorescence imaging and X-ray absorption spectroscopy of bladder sections confirmed that gallium arrived at the transitional epithelium, a potential site of uropathogenicE. coliinfection. Gallium and iron were similarly but not identically distributed in the tissues, suggesting that at least some distribution mechanisms are not common between the two elements. The results of this study indicate that gallium maltolate may be a suitable candidate for further development as a novel antimicrobial therapy for urinary tract infections caused by uropathogenicE. coli.

Download Full-text

The Extracellular Domain of the β2Integrin β Subunit (CD18) Is Sufficient forEscherichia coliHemolysin andAggregatibacter actinomycetemcomitansLeukotoxin Cytotoxic Activity

mBio ◽

10.1128/mbio.01459-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 5

Author(s):

Laura C. Ristow ◽

Vy Tran ◽

Kevin J. Schwartz ◽

Lillie Pankratz ◽

Andrew Mehle ◽

...

Keyword(s):

Escherichia Coli ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Integrin Signaling ◽

Β Subunit ◽

Wild Type ◽

Α Subunit ◽

Content Type ◽

Animal Pathogens ◽

Tract Infections

ABSTRACTTheEscherichia colihemolysin (HlyA) is a pore-forming exotoxin associated with severe complications of human urinary tract infections. HlyA is the prototype of the repeats-in-toxin (RTX) family, which includes LtxA fromAggregatibacter actinomycetemcomitans, a periodontal pathogen. The existence and requirement for a host cell receptor for these toxins are controversial. We performed an unbiased forward genetic selection in a mutant library of human monocytic cells, U-937, for host factors involved in HlyA cytotoxicity. The top candidate was the β2integrin β subunit. Δβ2cell lines are approximately 100-fold more resistant than wild-type U-937 cells to HlyA, but remain sensitive to HlyA at high concentrations. Similarly, Δβ2cells are more resistant than wild-type U-937 cells to LtxA, as Δβ2cells remain LtxA resistant even at >1,000-fold-higher concentrations of the toxin. Loss of any single β2integrin α subunit, or even all four α subunits together, does not confer resistance to HlyA. HlyA and LtxA bind to the β2subunit, but not to αL, αM, or αXin far-Western blots. Genetic complementation of Δβ2cells with either β2or β2with a cytoplasmic tail deletion restores HlyA and LtxA sensitivity, suggesting that β2integrin signaling is not required for cytotoxicity. Finally, β2mutations do not alter sensitivity to unrelated pore-forming toxins, as wild-type or Δβ2cells are equally sensitive toStaphylococcus aureusα-toxin andProteus mirabilisHpmA. Our studies show two RTX toxins use the β2integrin β subunit alone to facilitate cytotoxicity, but downstream integrin signaling is dispensable.IMPORTANCEUrinary tract infections are one of the most common bacterial infections worldwide. UropathogenicEscherichia colistrains are responsible for more than 80% of community-acquired urinary tract infections. Although we have known for nearly a century that severe infections stemming from urinary tract infections, including kidney or bloodstream infections are associated with expression of a toxin, hemolysin, from uropathogenicEscherichia coli, how hemolysin functions to enhance virulence is unknown. Our research defines the interaction of hemolysin with the β2integrin, a human white cell adhesion molecule, as a potential therapeutic target during urinary tract infections. TheE. colihemolysin is the prototype for a toxin family (RTX family) produced by a wide array of human and animal pathogens. Our work extends to the identification and characterization of the receptor for an additional member of the RTX family, suggesting that this interaction may be broadly conserved throughout the RTX toxin family.

Download Full-text

Ceftolozane-Tazobactam Activity against Phylogenetically Diverse Clostridium difficile Strains

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01670-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 7084-7085 ◽

Cited By ~ 1

Author(s):

Mark D. Gonzalez ◽

Meghan A. Wallace ◽

Tiffany Hink ◽

Erik R. Dubberke ◽

Carey-Ann D. Burnham

Keyword(s):

Urinary Tract ◽

Clostridium Difficile ◽

Urinary Tract Infections ◽

Anaerobic Bacteria ◽

Content Type ◽

Tract Infections ◽

High Mics

ABSTRACTCeftolozane-tazobactam (C/T) is approved for the treatment of complicated intra-abdominal and urinary tract infections and has varied activity against anaerobic bacteria. Here, we evaluate the activity of C/T against a phylogenetically diverse collection ofClostridium difficileisolates and report uniformly high MICs (≥256 μg/ml) to C/T.

Download Full-text