Beyond the usual suspects: emerging uropathogens in the microbiome age

Abstract

The advent of sensitive enhanced culture (metaculturomic) and culture-independent DNA-based (metagenomic) methods has revealed a rich collection of microbial species that inhabit the human urinary tract. Known as the urinary microbiome, this community of microbes consists of hundreds of distinct species that range across the entire phylogenetic spectrum. This new knowledge clashes with standard clinical microbiology laboratory methods, established more than 60 years ago, that focus attention on a relatively small subset of universally acknowledged uropathogens. Increasing reports support the hypothesis that this focus is too narrow. Single uropathogen reports are common in women with recurrent urinary tract infection (UTI), although wider disruption of their urinary microbiome is likely. Typical “UTI” symptoms occur in patients with “no growth” reported from standard culture and sometimes antibiotics improve these symptoms. Metaculturomic and metagenomic methods have repeatedly detected fastidious, slow growing, and/or anaerobic microbes that are not detected by the standard test in urine samples of patients with lower urinary tract symptoms. Many of these microbes are also detected in serious non-urinary tract infections, providing evidence that they can be opportunistic pathogens. In this review, we present a set of poorly understood, emerging, and suspected uropathogens. The goal is to stimulate research into the biology of these microbes with a focus on their life as commensals and their transition into pathogens

Full text

Beyond the usual suspects:
emerging uropathogens in
the microbiome age
Robert B. Moreland
1
, Brian I. Choi
1
, Wilson Geaman
1
,
Caroline Gonzalez
1
, Baylie R. Hochstedler-Kramer
1
,
Jerrin John
1
, Jacob Kaindl
1
, Nikita Kesav
1
, Jyoti Lamichhane
1
,
Luke Lucio
1
, Malika Saxena
1
, Aditi Sharma
1
, Lana Tinawi
1
,
Michael E. Vanek
1
, Catherine Putonti
2,3
, Linda Brubaker
4
and Alan J. Wolfe
1
*
1
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University
Chicago, Maywood, IL, United States,
2
Bioinformatics Program, Loyola University Chicago, Chicago,
IL, United States,
3
Department of Biology, Loyola University Chicago, Chicago, IL, United States,
4
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San
Diego, La Jolla, CA, United States
The advent of sensitive enhanced culture (metaculturomic) and culture-
independent DNA-based (metagenomic) methods has revealed a rich
collection of microbial species that inhabit the human urinary tract. Known as
the urinary microbiome, this community of microbes consists of hundreds of
distinct species that range across the entire phylogenetic spectrum. This new
knowledge clashes with standard clinical microbiology laboratory methods,
established more than 60 years ago, that focus attention on a relatively small
subset of universally acknowledged uropathogens. Increasing reports support
the hypothesis that this focus is too narrow. Single uropathogen reports are
common in women with recurrent urinary tract infection (UTI), although wider
disruption of their urinary microbiome is likely. Typical “UTI”symptoms occur in
patients with “no growth”reported from standard culture and sometimes
antibiotics improve these symptoms. Metaculturomic and metagenomic
methods have repeatedly detected fastidious, slow growing, and/or anaerobic
microbes that are not detected by the standard test in urine samples of patients
with lower urinary tract symptoms. Many of these microbes are also detected in
serious non-urinary tract infections, providing evidence that they can be
opportunistic pathogens. In this review, we present a set of poorly understood,
emerging, and suspected uropathogens. The goal is to stimulate research into
the biology of these microbes with a focus on their life as commensals and their
transition into pathogens
KEYWORDS
16S rRNA gene sequencing, anaerobe, antibiotic resistance, facultative anaerobe,
metaculturomics, urinary microbiome, urinary tract infection, uropathogen
Frontiers in Urology frontiersin.org01
OPEN ACCESS
EDITED BY
Evann Hilt,
University of Minnesota Twin Cities,
United States
REVIEWED BY
Robert Fredrick Potter,
Washington University in St. Louis,
United States
Krystal Thomas-White,
Evvy, United States
*CORRESPONDENCE
Alan J. Wolfe
awolfe@luc.edu
RECEIVED 26 April 2023
ACCEPTED 27 June 2023
PUBLISHED 26 July 2023
CITATION
Moreland RB, Choi BI, Geaman W,
Gonzalez C, Hochstedler-Kramer BR,
John J, Kaindl J, Kesav N, Lamichhane J,
Lucio L, Saxena M, Sharma A, Tinawi L,
Vanek ME, Putonti C, Brubaker L and
Wolfe AJ (2023) Beyond the usual
suspects: emerging uropathogens in the
microbiome age.
Front. Urol. 3:1212590.
doi: 10.3389/fruro.2023.1212590
COPYRIGHT
© 2023 Moreland, Choi, Geaman, Gonzalez,
Hochstedler-Kramer,John,Kaindl,Kesav,
Lamichhane, Lucio, Saxena, Sharma, Tinawi,
Vanek, Putonti, Brubaker and Wolfe. This is
an open-access article distributed under the
terms of the Creative Commons Attribution
License (CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that
the original publication in this journal is
cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms.
TYPE Review
PUBLISHED 26 July 2023
DOI 10.3389/fruro.2023.1212590

Introduction
More than a decade ago, reports began surfacing that challenged
the prevailing dogma that urine was typically sterile in the absence of
infection (1–10). These studies used high-throughput DNA
sequencing (metagenomics) and/or enhanced culture methods
(metaculturomics) coupled with matrix-assisted laser desorption/
ionization-time of flight (MALDI-TOF) mass spectroscopy (MS) to
detect and identify bacteria in urine samples obtained from diverse
sets of study participants. These modern sensitive detection methods
documented the presence of microbes in urines deemed “no growth”
by the traditional or standard urine culture methodologies used by
most clinical microbiological laboratories and highlighted the
presence of microbes not typically acknowledged as uropathogens
(11,12). These studies and others have resulted in a list of hundreds
of taxa. A few taxa are prevalent in individuals without lower urinary
tract symptoms. Many more taxa are present in asymptomatic
individuals but are more prevalent in those with symptoms
(Table 1,Appendix 1), including those typically associated with
urinary tract infection (UTI) and urgency urinary incontinence
(UUI), among others (9,10,13–21). For a recent review, see (22).
Statement of purpose
The purpose of this review is to highlight a set of poorly
understood, emerging, and suspected uropathogens. The intent is
to generate momentum for prospective and retrospective studies to
identify risk factors and improve antibiotic surveillance, especially
for those species that have no Clinical and Laboratory Standards
Institute (CLSI) standards.Wealsowishtoencourage
investigations into the pathophysiology of these microbes. Thus,
with a few exceptions, this review will focus on these lesser-known
microbes, including members of the families Aerococcaceae,
Actinomycetaceae, and Bifidobacteriaceae. Also discussed will be
members of the Streptococcus anginosus group (SAG) and
Enterococcus faecalis. While SAG members have long been
considered to be commensals, increasing evidence supports the
conclusion that they are more likely opportunistic pathogens (23).
Although long accepted as a pathogen, the comparatively well-
studied E. faecalis has become increasingly implicated in urinary
tract disorders and its pathophysiology within the urinary tract
remains understudied (24).
Other species we will review are anaerobes, specifically members
of the orders Eubacteriales and Bacteroidales. Traditionally,
anaerobes have not been considered to be uropathogenic (25,26).
However, in this age of metagenomics, metaculturomics, and
MALDI-TOF identification, this dogma is being reexamined (27).
The concept that oxygen is toxic to obligate anaerobes (28)doesnot
account for the strategies these microbes use to survive and flourish in
human organ niches (29,30), including the urinary tract.
Of organisms reviewed here, some are aerobes, some are
facultative anaerobes, and some are strict anaerobes. Many are
fastidious. As such, classical clinical laboratory diagnosis using
standard urine culture (SUC) methods would not detect most of
these potential uropathogens in the time frame or atmospheric
conditions of the assay (12,31). In contrast, all taxa reviewed herein
have been detected by metagenomic approaches, including 16S
rRNA gene sequencing and shotgun metagenomic sequencing (9,
10,14,15,18,19,32–34), and/or metaculturomic methods, such as
Expanded Quantitative Urine Culture (8,12,21)(Table 1). Despite
the discovery of some of these microbes as much as a century ago,
little is known about their biology.
Since much has been written about the most commonly accepted
and best studied uropathogens, including members of the family
Enterobacteriaceae (e.g., the genera Escherichia, Klebsiella,
Enterobacter,andProteus), and Gram-negative saprophytes
(Pseudomonas aeruginosa and Acinetobacter baumannii), we will
discuss them only briefly(35).Thesameistrueforthebetter-known
member(s) of the streptococci (S. agalactiae), the coagulase-positive
staphylococi (S. aureus), and the coagulase-negative staphyococci (S.
saprophyticus, S. epidermidis,andS. haemolyticus), as well as the yeast
genus Candida (C. albicans). We will not review the best-known
anaerobes, including but not limited to the genera Porphyromonas,
Sneathia,andPeptoniphilus. Finally, some urinary microbes have no
cell wall, most notably Mycoplasma and Ureaplasma (36). While
specialized techniques exist for the culture of these microbes (27,37,
38) and rapid molecular diagnoses have been reported for both (39), we
will not review these organisms here. For recent reviews on the taxa
mentioned above, see (24,40–46).
Commensals versus pathogens
The standard approach to treating UTI is based on Koch’s
postulates, which assumes a single organism is responsible for
pathogenicity, that this organism can be isolated from the diseased
tissue/fluid, be able to reproduce the disease state in a healthy
experimental system and be recovered afterward in pure culture
(47). This highly successful approach was responsible for the
elucidation of the bacterial pathogens of nineteen different diseases
from 1877 to 1906 including anthrax, bubonic plague, cholera,
diphtheria, pediatric diarrhea, bacterial pneumonia, gonorrhea,
syphilis, tuberculosis, typhoid fever, and whooping cough (47).
However, the discovery of the human microbiome and existence of
eubiotic states within human tissues such as the dermis, and the
respiratory, gastrointestinal, and urogenital tracts caused a rethinking
of the roles played by bacteria in health and disease (48,49).
An initial cataloging of human urinary bladder isolates revealed
149 distinct species ranging from aerobes and microaerobes to
facultative anaerobes and anaerobes (50). While all these microbes
can be identified by DNA-dependent methods, most are not
culturable or grow poorly under standard urine culture
conditions, while others overgrow because they possess adaptive
advantages (12). This is particularly true for facultative anaerobes
and is consistent with the genera Escherichia,Pseudomonas,
Klebsiella, Proteus, Staphylococcus, and Enterococcus being among
“The Usual Suspects”and common to standard urine culture
diagnoses (29,51). Microbes within the microbiome can be
grouped into six different classes: non-pathogen (not causing
disease), a pathogen (causing disease), a commensal (tissue
resident, benefiting the host) a symbiont (tissue resident,
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benefiting the host and is benefited from the host), a colonizer
(tissue resident and may or may not be disease causing) and a
pathobiont (tissue resident, generally beneficial but can cause
disease under special conditions) (52).
To understand microbial communities, one must first isolate
and characterize each of the individual species. Establishing the
commensal status of a species is much more difficult than reporting
pathogen case reports in tissues. Consequently, many of the reports
in the literature regarding the species reviewed here are pathological
reports from abscesses, blood cultures, or other disease states. The
science of understanding the interactions in a microbial community
between the six types of microbes mentioned above is in its infancy
(52,53). While reports of infections in tissues other than the urinary
tract provide only a worst-case capability of the capacity of these
species to cause or contribute to disease, it emphasizes the major
thrust of this review - to study these species in context and to begin
to understand their interaction within communities.
Commonly accepted uropathogens
Approximately 150 million people worldwide are diagnosed each
year with UTIs (54). These infections are thought to be caused by
uropathogenic bacteria, including but not limited to members of the
genera Escherichia,Pseudomonas,Klebsiella, Proteus, Staphylococcus,
and Enterococcus (51). Note that many of these species are in the
World Health Organization’s ESKAPE list of critical pathogens (55).
Escherichia coli is considered to be the most common cause of UTIs.
Other bacterial species that are commonly associated with UTI-like
symptoms include Pseudomonas aeruginosa, Klebsiella pneumoniae,
K. oxytoca, Enterococcus faecalis, E. faecium, Proteus mirabilis,
Proteus vulgaris, Staphylococcus aureus,andS. saprophyticus. The
yeast species Candida albicans also can cause UTI-like symptoms (56,
57). For example, a study of 727 hospitalized urological patients
diagnosed with nosocomial acquired UTI reported the most
commonly pathogens detected by SUC to be E. coli (31%), followed
by species of the genera Pseudomonas (13%), Enterococcus (10%),
Klebsiella (10%), Enterobacter (6%) and Proteus (6%) (58). These taxa
are all fast growing, non-fastidious, and able to thrive in the presence
of ambient oxygen (PO
2
150mmHg, 20kPa) (29,59), characteristics
that facilitate detection by SUC (60). Other microbes that are easily
detected by SUC include additional members of the Gram-negative
family Enterobacteriaceae, such as the genera Serratia, Citrobacter,
Morganella, Providencia,andPantoea. All have the capacity to be
pathogenic, but these genera are detected quite rarely. For example, in
a re-examination of several of our previous studies (21), they were
each detected in the catheterized (bladder) urine of less than 0.1% of
adult females (n=1007) and were rare even in those with UTI-like
symptoms (Table 1).
Saprophytes and other
environmental pathogens
Saprophytes are organisms that obtain their nutrients from
decaying organic material. As such, they tend not to be obligate
infectious agents of humans. However, they can be opportunistic
pathogens, causing wound and nosocomial infections, primarily in
immunocompromised individuals. A recent systematic review
found saprophytic bacteria to be implicated in hundreds of
infections in dozens of countries (42); 5% were UTIs. Most
affected individuals had comorbidities and the most common
species detected were Pantoea aglomerans,Klebsiella (formerly
Enterobacter) aerogenes, and Pseudomonas putida. The authors
warn that saprophytes such as these may become more common
in healthcare settings like other opportunistic environmental Gram-
negative bacteria, especially Acinetobacter baumannii and P.
aeruginosa (42).
A. baumannii and P. aeruginosa may cause nosocomial
infections, including nosocomial-acquired UTIs, especially in frail
or immunocompromised individuals (61). The World Health
Organization considers both priority-1 (critical) pathogens
because of their tendency to be resistant to carbapenems and
third generation cephalosporins, which are considered to be last
resort antibiotics (55,62). Multi-drug resistance and their biofilm-
forming capacity makes these infections difficult to treat with
antibiotic therapy (63). Whereas efforts to understand P.
aeruginosa and A. baumannii pathophysiology have been
extensive, uropathogenic strains remain understudied (42,63–67).
Fungi
Fungal UTIs are generally caused by members of the genus
Candida (68). Of these, the best known and most common UTI-
associated species is C. albicans. Other species include C. glabrata,
C. parapsilosis, and C. auris. The latter is an emerging pathogen
associated with UTIs that the CDC has added to its surveillance list
because it tends to be multidrug resistant, is difficult to detect using
standard clinical laboratory methodology, and has caused multiple
outbreaks in healthcare settings (69–71). Diabetes, catheterization,
hospitalization, and broad-spectrum antibiotics are risk factors for
Candida infections (72). Azole antifungals are the most common
treatment for symptomatic infections; however, increasing
resistance has been observed in clinical isolates. Wider
surveillance studies are severely needed (73).
The diagnostic criteria for detecting Candida in urine samples
are not standardized with continuing debate about reporting
thresholds (74,75). More problematically, typical clinical
laboratory methods of detection have poor sensitivity for Candida
species, even C. albicans. Several prospective studies that cultured
urine on the standard fungal medium, Sabouraud dextrose agar,
have reported greater numbers of non-C. albicans species than
standard urine culture methods (75–77). Thus, Candida species are
often not detected by standard clinical laboratory testing and
consequently are underreported.
The genus Staphylococcus
The genus Staphylococcus is comprised of more than 40 species
of Gram-positive, facultative anaerobic cocci (78–80). From a
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clinical microbiological diagnostic point, the genus can be divided
by coagulase activity (conversion of fibrinogen to fibrin). The most
common coagulase-positive Staphylococcus is S. aureus,a
commensal skin and upper respiratory tract coccus known to be a
potent, antibiotic-resistant opportunistic pathogen that can cause
diverse infections, especially skin and soft tissue infections and toxic
shock syndrome (80,81). As such, surveillance for this uropathogen
is high. In our re-examination of isolates obtained from catheterized
bladder urine samples of ~1000 adult females (21), S. aureus, the
most common coagulase-positive Staphylococcus, was detected in
urine but it was not prevalent (Table 1).
In contrast, coagulase-negative staphylococci (CoNS) are often
dismissed as contaminants (80,82–84). As opportunistic pathogens
in the urinary tract, CoNS are associated with UTIs, uncomplicated,
catheter-associated, and nosocomial (82,85–88). The ability for this
genus to acquire antibiotic resistance makes this group of microbes
an increasing threat to infectious disease control (81). We found
them to be quite prevalent, especially in adult females diagnosed
with UUI (Table 1). Of the 11 CoNS species detected, here we
review the 2 most prevalent species and 1 species commonly
associated with UTI (S. epidermidis,S. haemolyticus and S.
saprophyticus, respectively).
S. saprophyticus was first recognized as a causative microbe for
UTI in young females (82,86), and does appear to be associated
with young females of reproductive age. In contrast, it appears to be
very rare in older females; we have never detected it in this
population. However, the susceptibility of the host by age and
reproductive status remains unclear. Virulence factors, including
urease activity, have been described (82,83,89).
The most common CoNS in the urinary tract is S. epidermidis
(41,87). Whereas S. epidermidis infections are rarely life-
threatening, increasing antibiotic resistance and biofilm-forming
ability make them difficult to treat with antibiotics. Investigations
into the underlying molecular mechanisms have been performed
(87). Numerous case reports implicate S. epidermidis in UTIs,
especially in children (90–92), but the pathophysiology of urinary
isolates has yet to be explored.
S. haemolyticus is the second-most isolated CoNS from urine. It is
also common in blood cultures, especially from immunocompromised
patients. As such, it is considered an emerging multidrug-resistant
nosocomial pathogen (83,84). Of particular concern is the ability of S.
haemolyticus toacquiremultipleantibioticresistancegenes,making
antibiotic stewardship in the global treatment of UTIs an urgent public
health issue (84,93). The incidence of S. haemolyticus UTIs are
increasingly reported (84,88).
Emerging uropathogens
In contrast to several of the universally acknowledged
uropathogens, including but not limited to Serratia, Morganella,
Citrobacter,andE. faecium, many emerging or suspected
uropathogens are considerably more prevalent (Table 1). They
have been underappreciated for2majorreasons.First,as
mentioned above, many simply do not grow or grow poorly
under SUC conditions (60); however, they can be grown
(Appendix 2). Even E. faecalis tends to be underreported, in part
due to overgrowth of faster growing species (31). Second, before the
advent of MALDI-TOF MS, accurate identification of many species
was difficult (94) and many would have been dismissed as
contaminants (95–97). This dismissal has its consequences as was
suggested by investigators studying polymicrobial infections in
urinary sepsis where contamination could be ruled out (98,99).
The growth of microbes at less than 10
5
colony forming units per
milliliter (cfu/mL) has been noted and its significance debated since
the initial report of this standard for “infection”(100,101). On the
opposite end of the spectrum and demonstrating that some
microbes that do not grow on SUC, negative standard urine
cultures was reported in women with lower urinary tract
symptoms; with treatment, negative cultures and the symptoms
persisted (102), implying that some other causal factor and/or
uncultivated microbe was present.
Because its role in lower urinary tract health has been
underappreciated, we will review E. faecalis first and then a set of
emerging and suspected uropathogens.
The species Enterococcus faecalis
Less than 30 years after being recognized as a distinct taxon, the
clinical outlook on Enterococcus transitioned from harmless gut
commensal to a major public health concern. E. faecalis, the most
common clinical enterococcal species, is ubiquitously present in the
human gut microbiome where it plays a crucial role in nutrient
metabolism and maintenance of a heathy gut environment (103,
104). However, these microbes are also adept at adapting to novel
environments and transferring DNA to members of its own genus,
as well as other taxa. This latter characteristic has greatly
contributed to the worldwide spread of antibiotic resistance, the
most notable being the cassette of genes responsible for vancomycin
resistance, which is attributed to significantly increased mortality
rates (105).
With or without antibiotic resistance genes, enterococcal
infections at many body sites exhibit increased risk of
persistence and recurrence in comparison to other common
pathogens (106). Mechanisms underlying these chronic infection
phenotypes are largely unknown, as previous comparative
phylogenomic studies have been unable to differentiate between
clinical isolates from diverse infection types (107), most likely due
to insufficient isolate numbers and metadata. Despite this, E.
faecalis epidemiology and pathogenesis are most often studied
in the context of nosocomial infections. These investigations have
elucidated the presence and putative function of various virulence
factors, including proteins that facilitate colonization, aggregation,
and toxin production (107). The most severe enterococcal
nosocomial infection is bacteremia, which can lead to sepsis and
endocarditis. Even with appropriate treatment, this infection is
fatal in nearly 30% of cases (108). Enterococcal bacteremia has
previously been thought to originate via fecal contamination of
venous catheters or other medical devices; however, recent studies
have identified ascending bladder infections as a frequent prelude
to bacteremia (103,109).
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Patients with long-term indwelling urinary catheters have
increased risk for enterococcal bacteremia and sepsis. Therefore,
catheter-associated UTI (CAUTI), the most common enterococcal
nosocomial infection, is a main model system used to assess E.
faecalis behavior in the bladder. Studies have shown that E. faecalis
acts as a “founder species”in catheter colonization and that E.
faecalis presence in polymicrobial infections increases virulence of
other uropathogenic microbes, including P. mirabilis and E. coli
(110,111). CAUTI is thought to result from fecal contamination of
indwelling urinary catheters (103); however, the discovery of the
bladder microbiome raises the possibility that the bladder and
urethra could serve as endogenous reservoirs for E. faecalis,
making it possible that community-acquired UTI and subsequent
persistent bladder colonization could precede these chronic/
recurrent infection phenotypes.
Although E. faecalis is a recognized uropathogen underlying
community-acquired UTI, SUC has a detection rate of only 50%
relative to EQUC (31). This is because E. faecalis is often cultured
alongside other uropathogens or commensals, meaning it is either
(1) outcompeted during culture by hardier organisms, such as E.
coli, or (2) dismissed as “mixed morphologies”and reported as
contamination. Missed detection and empiric treatment of E.
faecalis-UTI imparts considerable risk, as the efficacy of many
antibiotics commonly used to treat UTI is currently being
debated for this species. The adaptability of this species and its
ability to acquire antibiotic resistance even to the newest antibiotics
has correlated with an increased number of cases reported
and represents a substantial health risk (24,35,111). These
include resistance to aminoglycosides (including gentamycin and
kanamycin), b-lactams, chloramphenicol, clindamycin,
daptomycin, erythromycin, flouroquinolones, oxazolidinones,
rifampin, streptomycin, tetracyclines, and tigecycline (24).
This is extremely problematic, as this species is known to have a
tropism for kidneys and once ascended is difficult to eradicate (103,
112). Recently, E. faecalis has also been associated with populations
experiencing recurrent UTI (31,113,114), defined as 3+ UTI in a
year or 2 within 6 months (115). These data suggest that E. faecalis
behavior in the bladder mimics that of common nosocomial
infections, strengthening the concern that this species could be
responsible for more severe infection phenotypes.
Thus far, no studies have reported how E. faecalis alters the host
bladder environment to promote its own persistent colonization.
Additionally, no studies have identified the virulence genes
necessary for persistent bladder colonization or urothelial cell
invasion. Understanding enterococcal behavior, especially in
connection to recurrent UTI, is crucial for developing more
efficacious treatment and prevention of severe infections, such as
bacteremia and sepsis.
The family Aerococcaceae
Understudied and under-detected, members of the family
Aerococcaceae are easily mistaken for other Gram-positive cocci
with similar morphologies and strict growth requirements. Their
taxonomy and identification have been fraught with inconsistency
and their relationship with human disease is frustratingly
mysterious (116). The increasing isolation of these organisms
from the urine of sick humans has earned them the title of
emerging uropathogens (116). Indeed, their ability to cause
serious disease, such as infectious endocarditis, makes them a
clear threat, and yet their ability to cause disease is still
uncharacterized. Below, we consider the genera Aerococcus,
Facklamia, and Globicatella.
Aerococcus.
The genus Aerococcus consists of several species, the majority of
which are associated with the urogenital tracts of livestock and
humans. The most prevalent and threatening species, however, is
Aerococcus urinae. Table 1 shows enrichment in adult females
diagnosed with UTI or UUI relative to asymptomatic controls
(detected in 11%, 34%, and 4%, respectively). Thus, A. urinae is
implicated with urine, especially in adult females with LUTS.
However, the circumstances and implications of how it ends up
there remains a mystery. The natural reservoir of the bacterium
is poorly described and the circumstances in which it
becomes pathogenic are uncharacterized. Currently, there is a
demonstrative need for greater investigation into the involvement
of A. urinae in urinary tract disorders such as UTI and UUI, as well
as invasive tissue infections. With increasing antibiotic resistance
observed in clinical isolates, A. urinae poses a growing threat to the
undiagnosed (and misdiagnosed) patient.
The first isolates of A. urinae came from the urine of patients
diagnosed with UTI (117). Originally thought of as a rare cause of
human infection, the bacterium has since seen a clear rise in
diagnoses and case reports alongside improvements in culture
techniques and identification technologies (118–121). While lethal
cases are rare, A. urinae has been identified in a variety of severe
disease complications, such as soft tissue infections and bacteremia,
all traced to a urological origin (120,122–124). Non-invasive
infections are associated with UTI and UUI in women (Table 1)
(9,21). However, enhanced culturing of urine from asymptomatic
participants also detects this species, complicating characterization
of A. urinae’sstatus, and suggesting that it is an opportunistic
pathogen (125).
Monoculture of A. urinae from urine is uncommon; instead, it
is often identified alongside several other species, contributing to its
dismissal as a contaminant. In cases of bacteremia, however, the
majority of infections are monomicrobial with significant risk for
endocarditis and septic embolization (126,127). Thus, it remains
unclear whether this bacterium works in concert with others or on
its own.
Risk factors for invasive infections include older age and
comorbid genitourinary diseases (121,124,128). In pediatric
settings, A. urinae has been reported as a cause for extraordinary
malodorous urine in boys with comorbid urogenital disorders as a
risk factor (129,130). Malodorous urine has been documented in
adult patients as well, having been described as ammoniacal and
“socially disabling”(120,131).
In all severe cases of infection, misidentification and lack of
resistance testing can lead to fatality (132,133). Currently, the
criterion standard for rapid identification in the clinical setting is
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via MALDI-TOF MS (125). However, A. urinae is easily missed on
routine urine culture and other bacteriological tests and, when
isolated, is often misidentified as streptococci, staphylococci, or
enterococci because they share many characteristics.
Whole genome sequencing and phenotypic characterization of
the organism has revealed substantial diversity within the A. urinae
species designation such that subdivision has been suggested (134–
136), although the clinical relevance of such divisions remains
unknown. Like other invasive uropathogens, A. urinae
demonstrates the ability to form biofilms on catheters and heart
tissue, as well as the ability to aggregate platelets (137–139). The
first UTI mouse model for A. urinae demonstrated a tropism for the
kidney, indicating a route for ascending infection despite
the bacterium being non-motile (140). Analysis for virulence
factors revealed genes predicted to be associated with adhesion
and anti-phagocytosis (135). Proteomic studies have supported this
finding, revealing an abundance of adhesive surface proteins
expressed on the bacterium’s surface (138,141). Unfortunately,
no genetic model currently exists to allow mechanistic studies into
these virulence factors.
With proper identification and susceptibility testing, antibiotic
therapy is generally effective for A. urinae infection. Isolates from
several studies have demonstrated susceptibilities to most antibiotics
used against Gram-positive organisms; however, resistances have
been indicated to fluoroquinolones, cephalosporins, trimethoprim-
sulfamethoxazole, and tetracycline (142–146). There is concern that
antibiotic resistance may be increasing; rising resistance has been
detected in wastewater samples (147). As with the related
streptococci, staphylococci, and enterococci, the possibility of
horizontal gene transfer of resistance genes may pose a significant
future risk. Another member of this genus, A. urinaeequi, has been
found to harbor a plasmid with tetracycline resistance and a
transposable element with vancomycin resistance (148,149).
As such, prudent stewardship based on careful microbial
identification is foundational for the diagnosis and treatment of A.
urinae infections.
Facklamia.
Facklamia species are challenging to accurately identify with
current microbiologic systems; they are often confused
with hemolytic streptococci (150). Thus, F. hominis is an
underrecognized pathogen that has been isolated from a variety
of clinical specimens, including bacteremia associated with brain
and soft tissue abscesses, endocarditis, necrotizing gangrene, and
ischemic stroke symptoms (151). It also has been associated with
pediatric pyelonephritis (152), acute cystitis and urosepsis (152), as
well as bacteremia associated with transurethral resection of the
prostate (153). Despite isolation from vaginal specimens and
urine, especially in adult females with UUI (Table 1), the role of
F. hominis as a commensal and the transition to opportunistic
pathogen has yet to be explored (151). Antibiotic resistances have
been demonstrated towards cephalosporins, erythromycin,
clindamycin, and trimethoprim-sulfamethoxazole (150,151).
More studies are needed to investigate mechanisms of virulence,
predisposing risk factors, and rates of infection.
Globicatella.
G. sanguinis was first isolated from human blood in 1978; more
recently it was proposed to be its own novel genus (154).
Globicatella infections have been associated with bacteremia,
septicemia, meningitis, infective endocarditis, wound infections,
and UTIs in humans on a sporadic basis (154–156). Isolates have
been detected in catheter-associated biofilms along with A. urinae
(138). As such, G. sanguinis is now considered to be an emerging
pathogen with an expanding disease spectrum, recently identified
from patients with endophthalmitis and osteomyelitis (157,158).
Since this species also has been considered to be a commensal
bacterium (159), it likely should be considered an opportunistic
uropathogen. Because of its close resemblance to streptococci and
aerococci under microscopic examination and morphologically on
blood agar, G. sanguinis is often misidentified. As a result, it can be
easily underestimated in clinical settings (160).
The Streptococcus anginosus
(Streptococcus milleri) group
The Gram-positive coccus Streptococcus anginosus was originally
described in 1906 (161). Early on, S. anginosus was thought to cause
strep throat, as it was observed to induce inflammation of the fauces,
the arched opening at the back of the mouth that leads to the pharynx
(161–163). The high degree of heterogeneity in phenotypic
characteristics between strains of S. anginosus (161,164,165)ledto
conflicting taxonomic characterizations during early studies before
Whiley and Beighton disambiguated S. anginosus into three separate
species: S. intermedius,S. constellatus,andS. anginosus. Together, these
species comprise the Streptococcus anginosus Group (SAG), also known
as the Streptococcus milleri group, which is one group within the larger
set of viridans streptococci (162). Today, it is well known that all three
members of SAG are part of the normal human flora, having been
isolated from the oropharynx, gastrointestinal tract, and vagina of
healthy individuals (23,162–164,166). As such, they are generally not
considered pathogens. However, in immunocompromised individuals,
opportunistic infections leading to bacteremia, pharyngitis, and
purulent infections have been reported (23). SAG also may
contribute to pulmonary exacerbations in cystic fibrosis patients
(167,168). They also contribute to cases of infective endocarditis
(169,170), and have been reported as complications of otitis media and
sinusitis and intracranial infections in children (171,172).
While SAG is primarily isolated from the upper respiratory
tract, an increasing number of studies have detected S. anginosus in
the urinary tract (21,173–176). Isolates of S. anginosus have been
identified in urine samples from individuals experiencing various
lower urinary tract symptoms; SAG members, particularly S.
anginosus are especially enriched in the bladder urine of adult
females diagnosed with UUI relative to asymptomatic controls
(49% versus 7%) (Table 1)(21).
Genetic sequencing of urinary isolates suggests that they belong
to a niche-specific clade that may have implications in disease (176).
An extensive list of virulence factors has been annotated in these
species; however, their role in establishing opportunistic infections
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is still unclear (177). Antibiotic resistance towards macrolides,
aminoglycosides, sulfonamides, and tetracyclines has been
observed (178–181) but the resistance profile of urinary isolates
has yet to be reported.
The family Actinomycetaceae
Members of the family Actinomycetaceae are a phylogenetically
diverse group of Gram-positive, facultatively anaerobic or micro-
aerophilic, branching rod-shaped bacteria. They are part of the flora
of the oropharyngeal, gastrointestinal, and genitourinary tracts of
humans and many animals (182). First identified in 1896 with A.
israelii, these rod-shaped bacilli form colonies with fungus-like
branched networks of hyphae, a characteristic that led to the
initially incorrect assumption that they were fungi. In most
healthy individuals, these organisms are commensal in the
mucosal epithelia of hollow organs. However, upon trauma or
disruption of the epithelial barrier, access to underlying tissues
can lead to actinomycoses characterized by a chronic,
granulomatous infectious disease (183–185).
Actinomyces
Members of the genus Actinomyces are Gram-positive,
pleomorphic, facultative anaerobic rods that exhibit some
branching (182,186). Actinomyces species have been identified in
catheterized bladder urine of asymptomatic adult females) but are
considerably more prevalent in those with UUI (5% and 23%,
respectively) (Table 1). Thus, under certain conditions, these
organisms could be opportunistic pathogens (187). For example,
initially isolated from urine and vaginal secretions, A. urogenitalis
has been reported in infections associated with long-term use of an
intrauterine device (183,185,188), in a case of bacteremia following
in vitro fertilization (189), and in an instance of bacteremia
associated with prolonged urinary retention (190). With case
reports making up the majority of recorded instances of these
organisms, it is clear that studies are needed to determine disease
risk factors and antibiotic resistances of infections.
Actinomyces-like organisms
The phylogenetic diversity of this family in combination with
new modern diagnostic techniques such as 16S rRNA gene
sequencing and MALDI-TOF have led to multiple taxonomic
revisions and the introduction of many novel species termed
Actinomyces-like organisms (ALOs). These include Actinotignum,
Gleimia, Schaallia, Trueperella, Varibaculum,andWinkia
(182,191).
Actinotignum.
This genus of facultatively anaerobic Gram-positive rods
consists of 4 species: Actinotignum schaalii, Actinotignum urinale,
Actinotignum sanguinis, and Actinotignum timonense (192–195).
A. schaalii and A. urinale were first described under the basonyms
Actinobaculum schaalii and Actinobaculum urinale, respectively
(192,193). However, based on the 16S rRNA gene sequence, a
remote relationship with the Actinobaculum suis type strain
was found (Soltys 50052), resulting in reclassification to the
Actinotignum genus (194,196).
Although first isolated from blood, both A. schaalii, A.
sanguinis, and A. urinale have since been isolated from urine. A.
schaalii has most often been reported in the context of UTI (197).
For example, it is reported to be an emerging uropathogen of elderly
people suffering from UTI with comorbidities (198,199). It also has
been detected in children with urinary tract disorders (200,201).
The genus as a whole has been reported to be significantly more
common in adult women with UUI than in unaffected controls (9,
21)(Table 1), but the species A. schaalii specifically has been found
at significantly higher mean abundances in adult women with UUI
compared to unaffected controls (202).
Other species have been associated with infections. A. urinale
was first isolated from human urine of patients with UTI (194);
however, it also has been isolated from human blood cultures (203).
A. sanguinis was first isolated from a human blood culture of a
patient with septicemia and has been co-isolated with Trueperella
bernardiae from breast abscesses in women (204). The first report of
A. timonense concerned an isolate from the urine of a 59-year-old
man with end-stage renal disease (195).
Like many of the species reviewed here, Actinotignum species
grow slowly under ambient atmospheric conditions typically used
by clinical microbiology laboratories; thus, they are often
overgrown by faster-growing bacteria. Furthermore, because these
species resemble commensal skin and mucosal species, they are
often mistakenly identified as contaminants (205). Also, until
recently, Actinotignum species were difficult to identify after
cultivation. However, the advent of molecular techniques has
resulted in increasing reports of A. schaalii in the context of
humaninfection(198,199). Further research is essential to
determine whether these Actinotignum species are uropathogens.
Gleimia.
Formerly belonging to the Actinomyces genus, the new Gleimia
genus consists of three members: G. europea, G. hominis, and G.
coleocanis. The first two have been isolated in humans and the latter
in dogs. Human isolates have been implicated in UTIs (182,206)
and have been suggested as a bladder cancer marker (207). They can
present clinically with persistent ear infections and recurrent soft
tissue infections (208–211), as well as abscesses of the neck, back,
feet, brain, and genital area in both men and women of various ages
(182,185,187,206,208,212–214). Recent cases have linked G.
europaea with necrotizing fasciitis (210,211) with a recent case
report of rapid infection progression and Fournier’s Gangrene
(215). Due to ineffective identification techniques, taxon
reclassification, and inadequate research, Gleimia species remain
misunderstood with few reports concerning their pathophysiology.
Schaalia.
Like Gleimia, a former member of the Actinomyces genus, S.
turicensis and S. radingae are Gram-positive, catalase- and urease-
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negative, anaerobic, filamentous bacilli (182,216) that have both
been isolated from catheterized urine. Originally isolated from a
perianal abscess, they were originally classed as CDC Coryneform
Group E, from which A. radingae and A. turicensis were purified
and characterized (216). After reassessment of phylogenetic
positioning and chemotaxonomic characteristics, these species
were reassigned to Schaalia along with eleven other species (191),
including S. meyeri and S. odontolytica, all part of the human
commensal urinary bladder microbiome.
S. turicensis is a commensal of the skin, gut, oral cavity, and
female urogenital tract (182) but is also an opportunistic pathogen.
Clinical isolates have been reported in bacteremia (217), purent
mastoiditis and meningitis (218), infection following rotator cuff
repair (219), gonococcal urethritis (220), and a perianal abscess
(216). The circumstances and conditions that transform S.
turicensis from commensal to pathogen remain to be elucidated.
Trueperella.
T. bernardiae is an emerging opportunistic pathogen in both
humans (204,221–229) and animals (230,231). In the 1980s,
isolates recovered from blood cultures, wounds, abscesses, and skin
infections were found to be similar by biochemical testing and
described using the provisional name CDC fermentative Coryneform
group 2 (CDC group 2) (230). CDC group 2 was formally assigned to
the species Actinomyces bernardiae based on 16S rRNA gene
sequencing and other features for strains recovered from infections
in the United States, Canada, and Switzerland (226). In 1997, following
reanalysis of the 16S rRNA gene sequences and after comparison with
species in the genus Actinomyces,A. bernardiae was assigned to the
genus Arcanobacterium (232). After reassessment of phylogenetic
positioning and chemotaxonomic characteristics, this species was
reassigned to Trueperella,alongwithA. abortisuis, A. bialowiezensis,
A. bonasi and A. pyogenes (233). Of these five organisms, only T.
bernardiae and T. pyrogenes have been reported in humans, all
associated with mild to severe infections and abscesses. As all 5
species have been reported as pathogens in animals, it has yet to be
established if T. bernardiae and T. pyrogenes are commensals in skin,
oropharynx, and urinary tract or are opportunistic zoonotic pathogens
of humans (225,231,233). The occurrence of T. bernardiae in
polymicrobial infections may reflect dependence of this organism on
nutrients provided by other species. Immunosuppressed patients
appear to be more at risk for infection by T. bernardiae (94).
Varibaculum.
The first member of this anaerobic, diphtheroid, Gram-positive
genus was initially characterized as a distinct species with
resemblance to the genus Actinomyces in 2003 (234). Case reports
have associated V. cambriensis in polymicrobial, anaerobic human
abscess infections (235). The source of these infections remains
unknown, and it is unclear if this microbe depends on one or more
partner species for survival or infection. Before the advent of
MALDI-TOF MS, accurate identification of V. cambriense in
routine clinical microbiology laboratories was difficult (233).
Thus, in the past, this species may have been dismissed as
contamination (97). Indeed, the use of more modern detection
methods have identified members of the genus Varibaculum in
human urine, as well as prostate and bladder cancer (236–238).
Whereas metaculturomic methods rarely detect this anaerobe, it is
frequently detected by metagenomic approaches. How
Varibaculum species cause disease remains poorly understood.
Winkia.
Actinomyces neuii was discovered in 1994 (239). Recently, it was
given its own genus Winkia (191). This catalase-positive
coccobacillus has been found in asymptomatic women (240) but
may be an opportunistic emerging pathogen in humans. Infections
include abscesses and infected atheromas (241), cellulitis (242),
endophthalmitis, and UTIs (185), as well as bacteremia, including
endocarditis (243). Isolates have also been implicated in neonatal
sepsis (244–246) and bacterial vaginosis (247). In all cases, how W.
neuii is mechanistically involved in these diseases is poorly
described. Antibiotic resistance to fluoroquinolones has been
observed (248), but wider studies into urinary isolate resistances
are needed. Like other Gram-positive rods, it is often dismissed as a
contaminant (249). We have found it to be highly enriched in adult
females with UUI relative to asymptomatic controls (28% and 3%,
respectively) (21)(Table 1).
The genus Corynebacterium
The Gram-positive genus Corynebacterium includes
approximately 80 recognized species. These are catalase-positive
rods with occasional swelling or club-like ends. The envelopes of
most but not all contain mycolic acid. Nine species are lipophilic
(able to metabolize lipids), asaccharolytic (unable to metabolize
carbohydrates), and strictly aerobic. The rest are non-lipophilic and
saccharolytic; some of these are fermentative facultative anaerobes,
while others are non-fermentative aerobes (250).
Although Corynebacterium species are typically commensals of
the mucous membranes of hollow organs and skin, some are
opportunistic pathogens. Many species have been isolated from
the bladder urine of asymptomatic adult females (50) but the genus
is particularly enriched in those diagnosed with UUI (8% and 52%,
respectively (21), (Table 1). Seven species that occur often and
either are or could be urinary tract opportunists are summarized in
Table 2 (250). Here, we review 2 of them: C. amycolatum and
C. urealyticum.
C. amycolatum
is a facultative anaerobic fermenter that is non-lipophilic (250,
251). It is unusual, as it lacks mycolic acid, which is common in
other coryneforms. Although a commensal of skin and mucous
membranes, C. amycolatum can be an opportunistic pathogen,
especially in immunosuppressed patents and nosocomial
environments. It has been isolated from blood cultures, cellulitis,
wounds, endocarditis, and peritonitis (250,253). A recent pan-
genomic study of drug resistant and commensal isolates of C.
amycolatum gave insight into the core genome and the transition
from commensal to pathogenic phenotype (262).
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C. urealyticum
is an asaccharolytic, lipophilic coryneform that expresses lipase
and strong urease activity (250,261,263). C. urealyticum is an
opportunistic nosocomial pathogen that can cause acute cystitis,
pyelonephritis, alkaline-encrusted cystitis, and encrusted pyelitis
(250). It has been associated with bacteremia, mainly in patients
with chronic urological diseases and its strong urease activity is a
major factor in urinary stone formation (260). Painful and
persistent pathologies occur associated with encrustations in the
kidney, ureters, and urethra due to alkalinization of urine from
metabolism of urea (261). It tends to be multi-drug resistant. In a
study of C. urealyticum infections in kidney transplant recipients,
between 40 to 85% of the isolates tested were resistant to
azithromycin, cefotaxime, chloramphenicol, ciprofloxacin,
clindamycin, erythromycin, gentamycin, norfloxacin, penicillin G,
or tetracycline (261) One non-antibiotic treatment relies on oral L-
methionine, which when metabolized acidifies urine (264,265). It is
unclear if this treatment is bactericidal or bacteriostatic, as in the
original report removing methionine resulted in return of the
uropathogens (264). C. urealyticum is also a zoonotic pathogen
associated with UTIs in dogs, cats and other animals (250).
The order Micrococcales
The order Micrococcales is comprised of eighteen families
including Dermabacteraceae and Micrococcaceae (191), comprised
of 3 and 19 genera, respectively. Several of these genera are detected
in human bladder urine including Dermabacter, Kokura,
Pseudoglutamicibacter, and Rothia (Table 1). Here, we review D.
hominis and both Pseudoglutamicibacter albus and P. cumminsii.
Dermabacter.
The Dermabacter genus contains three species: D. hominis, D.
jinjuensis,andD. vaginalis, of which only D. hominis has been found
in human catheterized urine (Table 1). First described in 1988 (266),
this Gram-positive, non-spore forming, non-acid fast, facultative
anaerobic short rod is considered to be a commensal of human
skin (267). However, D. hominis has been reported in diverse
clinically relevant scenarios, almost always as part of polymicrobial
communities in patients that are immunocompromised or suffering
with significant comorbidities, most often cardiovascular disease,
diabetes mellitus, and chronic kidney disease (267). Other reports
exist of its isolation from biopsies of bone and joint infections and
swabs of soft tissue infection (267), a case of trichobacteriosis axillaris
(268), a neck sebaceous cyst (269), blood cultures of patients with
bacteremia (270), peritoneal fluid from a patient with end stage renal
disease (271), recurrent abscesses (272), bone deposits from a patient
with chronic osteomyelitis (273), breast implant infections (274), and
cerebral abscess of a renal transplant patient (275). In one report, D.
hominis isolated from human semen was found to be capable of
forming a strong biofilm, which could potentially be a cause of
prostatitis (276). Thus, in immunocompromised patients or those
with comorbidities, D. hominis may be pathogenic. Although we have
detected it in the bladder urine of adult females with UTI and UUI
(Table 1), the relationship between this microbe and the urinary tract
remains unclear.
Pseudoglutamicibacter.
Originally assigned to Centers for Disease Control and
Prevention coryneform group B-1 and B-3 (277) and later the
genus Arthrobacter (278), the recently established genus
Pseudoglutamicibacter contains two species: P. cumminsii and P.
albus (279). It is unknown whether these species are commensal
microbes or opportunistic pathogens, and we have detected both
species in the bladder urine of both asymptomatic and affected adult
females (1% and 11%, respectively) (Table 1). However, most
samples collected from humans have been associated with severe
infections and abscesses, including infected amniotic fluid, chronic
cervicitis, chronic otorrhea, external otitis, calcaneus osteomyelitis,
sepsis, and UTI (277,280). Isolation sites have included blood,
bone, amniotic fluid, leg wounds, and urine (277,280).
Both P. cumminsii and P. albus are Gram-positive, mesophilic,
catalase-positive, obligate aerobe coccobacilli (278,279). P.
cumminisii is the most frequently encountered member of the
genus in human clinical specimens (280). A recent case study
identified P. cumminsii in the urine culture of a woman with UTI
(281). The first clinical specimen of P. albus was isolated from a
blood culture of a surgical patient with severe phlebitis (278). The
16S rRNA genes of P. cumminsii and P. albus share a high degree of
homology. This makes distinguishing these two organisms difficult
(279). Better differentiation will require whole genome sequencing
of isolates and better defined MALDI-TOF profiles.
The family Bifidobacteriaceae
The family Bifidobacteriales consist of 5 genera:
Bifidobacterium,Gardnerella,Alloscardovia,Scardovia and
Parascardovia (191). Of these, Bifidobacterium,Gardnerella and
Alloscardovia have been detected in human bladder urine (Table 1).
While the role of Bifidobacterium in colonizing the gastrointestinal
tract is well known (282), its role in the urinary tract remains
undefined. Gardnerella species are prevalent and abundant in the
urinary tracts of asymptomatic adult females but are somewhat
more prevalent in women with UUI (13% and 21%, respectively (9,
10)(Table 1). The role of G. vaginalis in bacterial vaginosis and a
link to UTI have been observed, but the mechanisms remain elusive
(82). Below, we review a lesser-known member of this family
Alloscardovia omnicolens.
Alloscardovia.
Several species belong to the genus Alloscardovia, but only A.
omnicolens has been described in human urine, especially from UUI
patients (Table 1). It is a Gram-positive, oxidase and catalase-
negative, non-spore-forming, anaerobic rod (283,284). While
originally considered to be a commensal of the gastrointestinal
tract and oral cavity, there is evidence that this microbe is clinically
significant and should not be ignored if found in clinical specimens,
especially if isolated from the urinary tract (285). The Alloscardovia
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TABLE 1 Frequency of Microbe Identification via Metaculturomics in Patients with and without LUTS
1
.
Microbe Total
N=1007
UTI
N=304
UUI
N=253
SUI
N=50
IC/PBS
N=49
Control
N=351
Acinetobacter 0.50% 0.00% 1.98% 0.00% 0.00% 0.00%
Actinobaculum 1.39% 0.99% 4.35% 0.00% 0.00% 0.00%
Actinomyces
2
10.13% 7.57% 22.53% 4.00% 6.12% 4.84%
Actinotignum 5.26% 3.95% 13.04% 6.00% 0.00% 1.42%
Aerococcus 16.29% 13.49% 36.36% 16.00% 10.20% 5.13%
Aerococcus urinae 14.20% 11.18% 33.60% 14.00% 8.16% 3.70%
Alloscardovia omnicolens 6.65% 4.93% 13.83% 8.00% 4.08% 3.13%
Bacillus 0.40% 0.33% 0.40% 0.00% 0.00% 0.57%
Bifidobacterium 5.06% 4.28% 9.88% 0.00% 8.16% 2.56%
Brevibacterium 3.28% 2.30% 8.70% 2.00% 2.04% 0.57%
Candida 3.18% 1.97% 7.11% 4.00% 2.04% 1.42%
Citrobacter 0.60% 1.64% 0.40% 0.00% 0.00% 0.00%
Corynebacterium 22.34% 15.13% 51.78% 26.00% 16.33% 7.69%
Cutibacterium 1.19% 0.99% 2.77% 0.00% 4.08% 0.00%
Dermabacter hominis 0.79% 0.33% 2.37% 2.00% 0.00% 0.00%
Enterobacter 1.79% 0.33% 5.53% 0.00% 0.00% 0.85%
Enterococcus 11.42% 8.88% 23.72% 8.00% 8.16% 5.70%
Enterococcus faecalis 11.12% 8.88% 22.92% 8.00% 8.16% 5.41%
Escherichia coli 24.83% 50.99% 25.69% 12.00% 8.16% 5.70%
Facklamia hominis 4.07% 1.32% 12.25% 2.00% 0.00% 1.42%
Gardnerella 14.10% 11.84% 20.95% 12.00% 2.04% 13.11%
Gemella 0.40% 0.00% 1.58% 0.00% 0.00% 0.00%
Globicatella 0.50% 0.00% 1.98% 0.00% 0.00% 0.00%
Haematomicrobium 0.30% 0.99% 0.00% 0.00% 0.00% 0.00%
Haemophilus 0.89% 0.33% 1.58% 4.00% 2.04% 0.28%
Klebsiella 5.76% 11.51% 6.72% 0.00% 2.04% 1.42%
Klebsiella pneumoniae 4.57% 8.22% 5.93% 0.00% 2.04% 1.42%
Kocuria 0.30% 0.00% 0.79% 0.00% 2.04% 0.00%
Lactobacillus 37.24% 35.53% 56.13% 42.00% 30.61% 26.21%
Micrococcus 3.38% 0.99% 7.11% 0.00% 2.04% 3.42%
Moraxella 0.30% 0.00% 0.79% 0.00% 0.00% 0.28%
Morganella 0.50% 0.33% 1.19% 0.00% 2.04% 0.00%
Neisseria 0.89% 0.66% 1.19% 6.00% 0.00% 0.28%
Oligella 1.19% 0.66% 3.56% 2.00% 0.00% 0.00%
Peptoniphilus 0.50% 0.00% 1.98% 0.00% 0.00% 0.00%
Prevotella 0.30% 0.00% 0.79% 2.00% 0.00% 0.00%
Proteus 2.38% 4.28% 3.95% 0.00% 0.00% 0.28%
Pseudoglutamicibacter 3.67% 1.64% 10.67% 0.00% 4.08% 0.85%
(Continued)
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TABLE 1 Continued
Microbe Total
N=1007
UTI
N=304
UUI
N=253
SUI
N=50
IC/PBS
N=49
Control
N=351
Pseudomonas aeruginosa 1.29% 1.97% 2.77% 0.00% 0.00% 0.00%
Rothia 1.79% 0.66% 2.77% 10.00% 0.00% 1.14%
Staphylococcus 22.44% 16.45% 45.85% 30.00% 20.41% 9.97%
Coagulase Negative Staphylococcus 21.05% 14.47% 45.06% 24.00% 20.41% 5.41%
Coagulase Positive Staphylococcus
3
2.38% 2.30% 3.56% 8.00% 0.00% 0.28%
Streptococcus 36.35% 28.29% 63.64% 40.00% 28.57% 24.22%
Streptococcus viridans grp. 13.90% 7.89% 22.92% 14.00% 14.29% 4.56%
Streptococcus anginosus grp. 23.24% 16.45% 48.62% 26.00% 12.24% 6.84%
Streptococcus agalactae 8.04% 7.89% 11.86% 10.00% 10.20% 4.84%
Trueperella bernardiae 2.09% 0.99% 5.53% 4.00% 0.00% 0.57%
Winkia neuii 9.43% 7.24% 21.74% 10.00% 4.08% 3.13%
Unknown 24.03% 17.76% 57.71% 18.00% 2.04% 9.12%
Arthrobacter 0.10% 0.00% 0.40% 0.00% 0.00% 0.00%
Aureimonas 0.10% 0.00% 0.40% 0.00% 0.00% 0.00%
Bacteroides 0.10% 0.00% 0.40% 0.00% 0.00% 0.00%
Blastocystis 0.10% 0.33% 0.00% 0.00% 0.00% 0.00%
Brevundimonas 0.10% 0.00% 0.00% 0.00% 0.00% 0.28%
Campylobacter 0.20% 0.00% 0.40% 0.00% 0.00% 0.28%
Comamonas 0.10% 0.00% 0.40% 0.00% 0.00% 0.00%
Dialister 0.20% 0.00% 0.40% 0.00% 0.00% 0.28%
Dolosigranulum 0.10% 0.33% 0.00% 0.00% 0.00% 0.00%
Eikenella 0.10% 0.00% 0.40% 0.00% 0.00% 0.00%
Finegoldia 0.20% 0.00% 0.40% 0.00% 2.04% 0.00%
Fusobacterium 0.10% 0.00% 0.40% 0.00% 0.00% 0.00%
Kytococcus 0.10% 0.33% 0.00% 0.00% 0.00% 0.00%
Propionimicrobium 0.20% 0.00% 0.79% 0.00% 0.00% 0.00%
Rhizobium 0.20% 0.00% 0.79% 0.00% 0.00% 0.00%
Saccharomyces 0.10% 0.00% 0.40% 0.00% 0.00% 0.00%
Serratia 0.10% 0.33% 0.00% 0.00% 0.00% 0.00%
Slackia 0.10% 0.00% 0.40% 0.00% 0.00% 0.00%
Stenotrophomonas 0.10% 0.00% 0.40% 0.00% 0.00% 0.00%
Veillonella 0.20% 0.00% 0.79% 0.00% 0.00% 0.00%
Weeksella 0.20% 0.00% 0.79% 0.00% 0.00% 0.00%
1
Isolates were isolated by EQUC and Identified via MALDI-TOF mass spectrometry. Frequency was calculated by dividing the total count of isolations of each genus/species/group by the total
number of samples in each group (N). Patients can be colonized by more than one species/genus at a time. When calculating frequency, redundancies in genus/group were considered. The
‘Unknown’grouping represents isolates unidentifiable via MALDI-TOF MS.
2
The values for the genus Actinomyces includes members of the newly reclassified genera Gleimia and Schaalia, as well true Actinomyces species.
3
The values for Coagulase-positive Staphylococcus are almost all S. aureus.
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genus was first described in 2007 by Huys and co-authors after
sampling various clinical sites, including the urethra, urine, blood,
abscesses of the lung and aorta, and tonsils (286). A. omnicolens has
been identified in urine cultures of bladder cancer patients with
concurrent UTI (285). It also has been considered the probable
cause of infection for at least one UTI (283) and a case of bacteremia
due to a UTI in a 70-year-old woman with advanced uterine cancer
(287). Therefore, A. omnicolens appears to be an opportunistic
pathogen. Antibiotic resistance to metronidazole and moxifloxacin
has been described (288,289).
The order Eubacteriales
The order Eubacteriales is comprised of at least 25 families, all
anaerobes. Of these families, members of Clostridiaceae (290,291)
and Peptostreptococcacae (40,292) are reviewed here. Anaerobes are
not detected by SUC (27). Oxygen toxicity complicates the collection
and culturing these microbes (28,30), making it difficult to obtain
sufficient material for characterization (27,293). However, with the
advent of molecular diagnostic techniques and enhanced culture
methods, the role of anaerobes in both the commensal flora and as
opportunistic pathogens is becoming recognized (27).
Thomasclavelia ramosum
Is a Gram-positive obligate anaerobic bacillus with the ability to
hydrolyze esculin (290,293–297). As such, it is rarely cultured, even
by EQUC, but it is observed by metagenomic approaches.
Discovered in 1898, it was named Bacillus ramosum then
renamed Ramibacterium ramosum (295,297). The demonstration
of sporulation led to its reclassification as Clostridium ramosum
(294,297). Further dissections of the genus Clostridium, using a
combination of genetic markers, led to another name change, this
time to Erysipelatoclostridium ramosum and most recently to
Thomasclavelia ramosum (290,293,296).
While found as part of the commensal flora in the
gastrointestinal and urinary tracts, this organism has been
documented in infections, such as appendicitis, blood, brain
abscess, bacteremia, joint infections, and pulmonary gangrene
(295,297,298). It also is one of the few sporulating bacteria
detected in the urinary microbiome. Further study is warranted to
understand how this commensal becomes an opportunistic and
potent pathogen.
Peptostreptococcus anaerobius.
Originally described in 1936, the genus Peptostreptococcus consists
of four species, P. anaerobius, P. canis, P. russellii,andP. stomatis (40,
292,299). These are Gram-positive anaerobic cocci; thus, they are
rarely cultured but are frequently detected by metagenomic
approaches. They have weak fermentative and proteolytic
metabolisms. Consequently, it may be symbiotic with other
organisms from which it derives nutrients (300). Indeed, P.
anaerobius has been isolated most often from polymicrobial
infections of soft tissue, bone, brain, implant-related and respiratory
tract infections (40,292,299). P. anaerobius is also one of the most
common Gram-positive, anaerobic cocci isolated from infections of the
female urogenital tract and the abdominal cavity (292). Thus, while P.
anaerobius is probably a commensal of the gastrointestinal, vaginal,
and urinary tracts, it can be an opportunistic pathogen, particularly
within polymicrobial infections.
The order Bacteroidales
The order Bacteroidales is comprised of 17 families. The best
known are Bacteroidaceae and Prevotellaceae. The latter family
consists of Gram-negative anaerobes split into four genera:
Hallella,Paraprevotella,Prevotella,andAlloprevotella (301).
Below, we will review a few species.
Prevotella.
The genus Prevotella consists of 55 distinct species of Gram-
negative coccobacilli anaerobes that are commonly found in the
oral, gastrointestinal, and urogenital tracts of humans and animals.
TABLE 2 Selected bladder urine commensal Corynebacteria reported as opportunistic pathogens.
Organism Characteristics Urease Clinical Conditions/Isolates References
C. amycolatum Non-lipophile, Aerobe + Blood culture, cellulitis, endocarditis, mastitis, peritonitis, sepsis, wounds (250–253)
C. aurimucosum Non-lipophile, Facultative
anaerobe
–Blood culture, complications of pregnancy, UTI (249,250,254)
C.
glucuronolyticum
Non-lipophile, Facultative
anaerobe
+ Chronic prostatitis, cystitis, infertility, persistent urethritis (250,255,256)
C. minutissimum Non-lipophile, Aerobe,
Facultative anaerobe
+ Bacteremia, meningitis, endocarditis, cellulitis, abscesses, peritonitis,
pyelonephritis
(250,252)
C. riegelii Non-lipophile, Facultative
anaerobe
+ Blood cultures, urosepsis, UTI (250,257,258)
C.
tuberculostearicum
Lipophile, Facultative
anaerobe
–Abscesses, blood culture, mastitis, peritonitis (250,252,259)
C. urealyticum Lipophile, Microaerophile + Acute cystitis, alkaline encrusted cystitis, encrusted pyelitis, endocarditis, kidney
and bladder stones, pyelonephritis, UTI
(250,260,261)
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It was originally proposed to characterize the moderately
saccharolytic, oral Bacteroides species (302). Until recently, the
lack of characteristic phenotypic and biochemical traits had
hampered identification at the species level among this group of
obligatory anaerobes. They are rarely cultured, but the availability of
16S rRNA sequence analysis has improved detection, and thus the
number of recognized Prevotella species has increased over the last
few years (303). Recently, a genomic and functional analysis of the
55 phenotypically, ecologically and functionally diverse species
comprising Prevotella identified 7 distinct clades and thus
reassignment across 7 genera, with 4 of them being new genera:
Segatella,Hoylesella,Leyella and Palleniella (304). Below, we review
Prevotella bivia and Hoylesella timonensis.
Prevotella bivia.
Previously classified as Bacteroides bivius,P. bivia is commonly
found in the human vaginal microbiome (305). Though normally a
commensal, P. bivia has pathogenic potential to trigger severe
infection and induce tissue destruction, especially when there is
excess estrogen and with the synergistic cooperation of other species
(306). P. bivia is one of the most frequently isolated anaerobic
bacteria in cases of bacterial vaginosis. The presence of P. bivia
creates an environment that facilitates growth of Peptostreptococcus
anerobius (300) and Gardnerella vaginalis (307). P. anaerobius
growth is enhanced with production of certain amino acids by P.
bivia. Likewise, G. vaginalis growth is enhanced with production of
ammonia by P. bivia.
P. bivia is one of the most frequently isolated bacteria in women
with pelvic inflammatory disease, as noted in a retrospective, cross-
sectional study (308), It has also been implicated in cases of recurrent
UTIs, osteomyelitis (309), osteitis (310), endocarditis (311),
necrobacillosis (312), sinusitis (313), wound infections from animal
bites (314,315), intracranial abscesses (316), periodontal and tubo-
ovarian abscesses (317), and adverse pregnancy outcomes such as
preterm labor (318). The virulence factors of P. bivia are not fully
understood, but research suggests that they may includeadhesins that
allow the bacteria to attach to host cells, enzymes that degrade host
tissue, and toxins that damage host cells and stimulate inflammation.
As with other members of the genus Prevotella, antibiotic resistance is
becoming an increasing concern; the most common are amoxicillin-
clavinate, clindamycin, and moxifloxacin (319). Thus, further
research into P. bivia is warranted.
Hoylesella timonensis.
Prevotella timonensis was first isolated from a human breast
abscess (320). After reassessment of phylogenetic positioning and
chemotaxonomic characteristics, this species was reassigned to
Hoylesella (304). Like the previously described anaerobes, H.
timonensis is rarely cultured but detected often by metagenomics.
The breast abscess isolate mentioned above ferments glucose,
maltose, and lactose. It also hydrolyzes esculin but is urease and
catalase negative. Although the species has most often been isolated
from cutaneous/soft tissue abscesses and bone infections, it is also
prevalent in human genitourinary samples, including from urine
(304,321). While H. timonensis may be a commensal organism in
the genitourinary tract, it has been associated with bacterial
vaginosis (322). Thus, some evidence supports its role as an
emerging opportunistic pathogen (321,322).
Concluding remarks
This review provides a robust description of lesser-known
microbes to support our recommendation that our understanding
of uropathogens should go beyond the “usual suspects.”Current
clinical diagnosis is hampered by limitations in what clinical
microbiologists detect in culture in as little incubation time as
possible, most often under atmospheric oxygen conditions (323).
This current approach underreports fastidious, slow growing, and
anaerobic bacteria, many of which are generally excluded as
uropathogens despite evidence to the contrary (12,27,292). The
clinical consequences include the common scenario of repeated
negative standard urine culture results despite relevant, persistent
symptoms (102). Common sense should lead one to suspect that
some undetected agent(s) play(s) a role in these persistent
symptoms and the most likely candidates are fastidious, slow
growing and/or anaerobic bacteria. The standard method
dismisses, underreports, or does not detect these microbes but
they are repeatedly detected by more sensitive metaculturomic
(enhanced culture-dependent) or metagenomic (culture-
independent, DNA-based methods) (324).
None of the reviewed species were discovered recently. For
example, Thomasaclava (formerly Clostridium)ramnosum dates
back more than a century, while others (e.g., A. urinae) were
discovered at least 10 years ago. Yet, little is known of their
pathophysiology. Even their phylogeny is poorly understood, as
highlighted by the plethora of name changes (191,293,304). As
microbial detection technologies have improved, especially with the
advent of MALDI-TOF MS, so too have the detection and reporting
of these microbes. However, description of these microbes in
relation to disease should not be confined to sporadic case reports
as has been the case so far.
This review is a call to action to fill this knowledge gap, to begin
studies designed to determine first their functioning as commensals
and then their transition to opportunistic pathogens. Both
retrospective and prospective studies are greatly needed to
determine risk factors for symptomatic infections, especially for
microbes that have the ability to cause severe complications that
might be entirely preventable with proper and early diagnosis. The
global rise in antibiotic resistance is well established but only for
microbes under active surveillance. Until the resistance profiles of
urinary isolates are better reported, patients will continue to
experience therapy failures. Thus, as long as we remain blind to
the activities and capabilities of these emerging uropathogens,
preventable damage will continue to afflict patients and will most
definitely worsen as these microbes continue to evolve.
Author contributions
AW conceived of the manuscript. All authors contributed to the
article and approved the submitted version.
Moreland et al. 10.3389/fruro.2023.1212590
Frontiers in Urology frontiersin.org13

Funding
This work is funded by internal funds to AW. No funding
source had a role in the process of writing this manuscript.
Acknowledgments
We acknowledge the efforts of the clinical and scientific team
members of the Loyola Urinary Education and Research
Collaborative (LUEREC).
Conflict of interests
LB discloses editorial stipends from JAMA, Female Pelvic
Medicine & Reconstructive Surgery, and UpToDate. AW discloses
advisory board membership for Pathnostics and Urobiome
Therapeutics, funding from Pathnostics, the Craig Neilsen
Foundation, NIH, and an anonymous donor.
The remaining authors declare that the research was conducted
in the absence of any commercial or financial relationships that
could be construed as a potential conflict of interest.
The author AW declared that they were an editorial board
member of Frontiers, at the time of submission. This had no impact
on the peer review process and the final decision.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at:
https://www.frontiersin.org/articles/10.3389/fruro.2023.1212590/
full#supplementary-material
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