AHA/ACC SCIENTIFIC STATEMENT (2024)

March 2024

AGA Clinical Practice Update on Diet and IBD

529

feel that nutrition is either not being prioritized in their care

and intestinal remodeling resulting from gut inflammation,

or is being overlooked, and often report that dietary advice

patients with IBD can be instructed to modify the texture of

from non-RD practitioners is heterogenous and conflict-

fibrous foods by cooking, blending, and thoroughly chewing

ing.⁶⁹

This results in self-directed nutrition changes,

fruits and vegetables, which will allow them to better

resulting in unnecessary dietary restriction and increased

tolerate a healthy diet over the lifespan.

risk of developing malnutrition.⁵⁷ RDs are fundamental

When there is active inflammation and/or stricturing com-

members of the multidisciplinary IBD care team, as they

plications of CD, liquid nutrition formulas have demonstrated

have expertise in diagnosis and management of malnutri-

efficacy. Complete dietary modification with EEN using

tion, including specific protein, macronutrient, vitamin, and

commercially available liquid nutrition formulas may induce

micronutrient requirements, which vary in different phases

remission in CD, with the strongest evidence in children. The

of illness.⁷⁰ Ideally, referral to an RD should not be deferred

complete avoidance of regular food for a prolonged time period

until the consequences of uncontrolled disease, such as

is challenging for many patients with IBD, but clinical remission

malnutrition, become unmanageable. RDs can also play a

can be maintained with a staged reintroduction of foods. In

key role in prevention of extraintestinal complications of

patients with CD and obstructive complications necessitating

IBD, including dietary modification to prevent enteric

surgery, preoperative therapy with liquid nutrition can improve

hyperoxaluria and development of kidney stones.

nutritional status and improve operative outcomes.

PN and EN support requires a specialized practice that

Intravenous nutrition with fluids, macronutrients, vita-

necessitates the expertise of an RD. The role of the RD is to

mins, and minerals maintains an important, lifesaving role

assist the multidisciplinary team with appropriate nutrition

in the short-term management of patients with IBD during

support route selection; prescribing adequate energy, pro-

acute inflammatory and obstructive complications when the

tein, and micronutrient needs; monitoring patients

gut is no longer functioning and able to safely handle oral

throughout the duration of the treatment; adjusting the

intake. Patients with IBD with SBS will benefit from home

nutrition prescription when indicated; educating the patient

fluid and nutritional support and treatment with glucagon-

on safe administration and compliance with EN and PN

like peptide-2 medications, which enhance intestinal adap-

support, as well as guiding the patients and their care team

tation, and weaning from PN should be considered in long-

on the appropriate transition back to a regular oral intake.

term management.

Best Practice Advice 12: Breastfeeding is associ-

Dietary advice needs to be tailored to an individual IBD

ated with a lower risk for diagnosis of IBD during

patient’s nutritional status and goals, which will vary over

childhood. A healthy, balanced, Mediterranean diet rich

time. Implementing the more complex nutritional strategies

in a variety of fruits and vegetables and decreased

for IBD management will be best achieved by means of

intake of ultraprocessed foods have been associated

collaborative interdisciplinary practice between gastroen-

with a lower risk of developing IBD.

terologists and RDs.

Numerous studies have investigated potential predis-

posing and protective factors for developing IBD. Such

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CRediT Authorship Contributions

Jana G. Hashash (Conceptualization: Lead; Data curation: Equal; Writing -

meta-analysis: breastfeeding and the risk of Crohn’s

original draft: Equal; Project administration: Lead; Supervision: Equal;

disease and ulcerative colitis. Aliment Pharmacol Ther

Visualization: Equal)

Jaclyn Elkins (Data curation: Equal; Writing - original draft: Equal)

2017;46:780-789.

James D. Lewis (Writing - review & editing: Equal; Supervision: Equal)

73.

Ananthakrishnan AN, Khalili H, Konijet GG, et al.

David G. Binion (Writing - original draft: Supporting; Writing - review &

A prospective study of long-term intake of dietary fiber

editing: Lead; Supervision: Equal; Visualization: Equal)

and risk of Crohn’s disease and ulcerative colitis.

Conflicts of interest

Gastroenterology 2013;145:970-977.

These authors disclose the following: James D. Lewis consulted/served on an

advisory board for Eli Lilly and Company, Samsung Bioepis, UCB, Bristol-

74.

Narula N, Chang NH, Mohammad D, et al. Food pro-

Myers Squibb, Nestlé Health Science, Merck, Celgene, Janssen

cessing and risk of inflammatory bowel disease: a sys-

Pharmaceuticals, Bridge Biotherapeutics, Entasis Therapeutics, AbbVie,

tematic review and meta-analysis. Clin Gastroenterol

Pfizer, Gilead, Arena Pharmaceuticals, Protagonist Therapeutics, Amgen,

Sanofi, and Scipher Medicine. He has had research funding from Nestlé

Hepatol 2023;21:2483-2495.e1.

Health Science, Takeda, Janssen Pharmaceuticals, and AbbVie. He has

received educational grants from Takeda and Janssen. He has performed

legal work on behalf of generic manufacturers of ranitidine, including L.

Received April 23, 2023. Accepted November 5, 2023.

Perrigo Company, Glenmark Pharmaceuticals Inc, Amneal Pharmaceuticals

LLC, Aurobindo Pharma Switzerland, Inc, Dr. Reddy’s Laboratories, Inc,

Correspondence

Novitium Pharma, Ranbaxy Inc, Sun Pharmaceutical Industries, Inc, Strides

Address correspondence to: Jana G. Hashash, MD, MSc, Division of

Pharma, Inc, and Wockhardt Switzerland LLC. He owns stock in Dark

Gastroenterology and Hepatology, Mayo Clinic,

4500

San Pablo Road,

Canyon Labs. David G. Binion has received research funding from AbbVie,

Jacksonville, Florida 32224. e-mail: AlHashash.Jana@mayo.edu.

Merck, and Takeda. The remaining authors disclose no conflicts.

Stroke

AHA SCIENTIFIC STATEMENT

Diagnosis and Management of Cerebral Venous

Thrombosis: A Scientific Statement From the

American Heart Association

Gustavo Saposnik, MD, MPH, PhD, FAHA, Chair; Cheryl Bushnell, MD, MHS, FAHA, Vice Chair; Jonathan M. Coutinho, MD, PhD;

Thalia S. Field, MD, MHSc; Karen L. Furie, MD, MPH, FAHA; Najibah Galadanci, MBBS, MPH, PhD; Wayneho Kam, MD;

Fenella C. Kirkham, MD; Norma D. McNair, RN, PhD; Aneesh B. Singhal, MD, FAHA; Vincent Thijs, MD, PhD, FAHA;

Victor X.D. Yang, MD, PhD; on behalf of the American Heart Association Stroke Council; Council on Cardiopulmonary, Critical

Care, Perioperative and Resuscitation; Council on Cardiovascular and Stroke Nursing; and Council on Hypertension

ABSTRACT: Cerebral venous thrombosis accounts for 0.5% to 3% of all strokes. The most vulnerable populations include

young individuals, women of reproductive age, and patients with a prothrombotic state. The clinical presentation of cerebral

venous thrombosis is diverse (eg, headaches, seizures), requiring a high level of clinical suspicion. Its diagnosis is based

primarily on magnetic resonance imaging/magnetic resonance venography or computed tomography/computed tomographic

venography. The clinical course of cerebral venous thrombosis may be difficult to predict. Death or dependence occurs in

10% to 15% of patients despite intensive medical treatment. This scientific statement provides an update of the 2011

American Heart Association scientific statement for the diagnosis and management of cerebral venous thrombosis. Our

focus is on advances in the diagnosis and management decisions of patients with suspected cerebral venous thrombosis.

We discuss evidence for the use of anticoagulation and endovascular therapies and considerations for craniectomy. We also

provide an algorithm to optimize the management of patients with cerebral venous thrombosis and those with progressive

neurological deterioration or thrombus propagation despite maximal medical therapy.

Key Words: AHA Scientific Statements ◼ anticoagulants ◼ headaches ◼ intracranial thrombosis ◼ seizure ◼ sinus thrombosis ◼ venous thrombosis

erebral venous thrombosis (CVT) is the presence of

This scientific statement synthetizes the clinical

a blood clot in the dural venous sinuses, the cerebral

presentation, predisposing factors, advances in imag-

veins, or both.¹ Among those with stroke, CVT repre-

ing modalities and therapies, and management of CVT

sents only 0.5% to 3%.² Registry-based and cohort stud-

in special populations (pediatric, pregnancy and puer-

ies suggest that CVT affects predominantly individuals

perium, and vaccine-induced CVT). This document

<55 years of age, with two-thirds occurring in women.²

is strengthened by new evidence since our previous

With regard to location, the most commonly affected

publication in 2011.1 Future areas of research are

sinuses are illustrated in Figure 1.^1-3

highlighted.

Overall, patients with CVT have a favorable out-

come. Most patients with CVT nowadays survive with-

CLINICAL PRESENTATION

out physical disability, but chronic symptoms, which

negatively affect quality of life, are not uncommon.

Presenting symptoms of CVT can be due to increased

Most common factors associated with poor prognosis

intracranial pressure or focal parenchymal injury, with

include advanced age, active cancer, decreased level of

or without mass effect.¹ Headache is the most com-

consciousness, and intracerebral hemorrhage, among

mon symptom of CVT, occurring in nearly 90% of

others.^1,4,5

cases.⁴ Other signs and symptoms related to intracranial

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STR.0000000000000456.

Stroke is available at www.ahajournals.org/journal/str

Stroke. 2024;55:e00-e00. DOI: 10.1161/STR.0000000000000456

TBD 2024 e1

Saposnik et al

Diagnosis and Management of Cerebral Venous Thrombosis

Figure 1. Anatomy of the cerebral venous system and distribution of CVT.

Prevalence of sinus involvement in CVT. Percentages may be >100% because many patients may have >1 sinus involved.^1-3 Please note that

internal jugular vein thrombosis represents its concomitant prevalence with CVT (not in isolation). CVT indicates cerebral venous thrombosis.

pressure include nausea, transient visual obscurations

can be associated with CVT.^1,4,7,16 Other transient provoking

or vision loss (13%-27%), papilledema, and diplopia

factors commonly reported in previous series include infec-

(6%-14%).^2,4,6,7 Other cranial neuropathies can also

tions (COVID-19, head and neck infections),^17-19 dehy-

occur from increased intracranial pressure (6%-11%).

dration,^2,20 other medications such as corticosteroids and

Approximately 20% to 40% have seizures at the time

l-asparaginase, and vaccine-induced thrombotic thrombo-

of presentation, and 20% to 50% have focal neurologi-

cytopenia (VITT).^1,4 Mechanical provoking factors such as

cal deficits.^2,4,6-9 Encephalopathy and coma have been

head trauma, neurosurgical procedures, and compressive

reported in up to 20%.^2,4,6-8 Symptoms tend to occur more

lesions such as meningiomas impinging on venous sinuses

insidiously than in other stroke types, and the majority

are also associated with CVT.^1,4,21

will present >48 hours after onset. A minority may have

more acute presentations with thunderclap headache or

LONG-TERM SYMPTOMS AND CVT

subarachnoid hemorrhage (<5%) or acute onset of focal

neurologic deficits (5%-40%).^2,4,6-8 Further details are

RECURRENCE

summarized in Supplemental Table 1.

Overall, 80% to 90% of patients with CVT achieve func-

tional independence (modified Rankin Scale score of

0-2).^1,4,5 However, several studies reported a high preva-

PREDISPOSING FACTORS

lence of residual symptoms related to cognition, mood,

Predisposing factors for CVT are identified in the major-

fatigue, and headache, which may impede return to pre-

ity of those with the disease and may be transient or

vious level of activity.^22-24 A prospective cohort from a

chronic (Table).^10,11 Rates of CVT are highest in younger

Canadian randomized trial found that although 72% of

women, with both oral contraception and pregnancy/

individuals with CVT remained functionally independent

puerperium being major risk factors.^12,13 Oral contracep-

at the time of their presentation, there was an overall

tion and hormonal therapies¹⁴ (primarily those containing

substantial burden of headache, fatigue, low mood, and

estrogen-based formulations) may increase the odds of

impaired cognitive performance.²⁵ A retrospective study

CVT nearly 8-fold,¹¹ with possible additional synergistic

from China including 303 patients with CVT who were

effects with obesity.¹⁵ Other well-established risk factors

employed or students before their index event found that

include acquired thrombophilias such as antiphospholipid

42% had not returned to work or school at 6 months,

antibody syndrome, JAK2 mutations, malignancy, particu-

despite 87% reaching functional independence at the

larly myeloproliferative disorders, and autoimmune disease,

time of assessment.²⁶

including Behçet and inflammatory bowel disease. Genetic

Epilepsy may affect >10% of individuals with CVT,

thrombophilias such as protein C and protein S deficiency,

with risk factors including seizures at the time of onset,

factor V Leiden, and prothrombin G20210A polymorphism

decreased level of consciousness or focal deficits,

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Diagnosis and Management of Cerebral Venous Thrombosis

Table. Predisposing Factors or Medical Conditions Associated With CVT

Transient

Chronic

Sex-specific and transgender hormonal

Oral contraceptive (54%-71%)

Hormone replacement therapy

treatment

Pregnancy/postpartum (11%-59%)

Hormone therapy for transfeminine or transmasculine individuals

Hormone replacement therapy (4%)

Other morbidity

Head and neck infections (8%-11%)

Obesity (23%)

Dehydration (2%-19%)

Anemia (9%-27%)

Anemia

Other systemic diseases (thyroid disease, nephrotic syndrome, inflam-

matory bowel disease; 1%-2%)

Sepsis

Respiratory infections

COVID-19 (7.6%)

Other medications

Corticosteroids

l-Asparaginase

Thalidomide

Tamoxifen

Malignancy

Myeloproliferative disorders (2%-3%)

Other malignancy (7%)

Autoimmune

Antiphospholipid antibody syndrome (6%-17%)

Connective tissue disease (systemic lupus erythematosus, Behçet

disease, sarcoidosis; 1%)

Other genetic thrombophilia (31%-41%)

Prothrombin 20210A mutation

Factor V Leiden mutation

MTHFR (C677T) polymorphism

Antithrombin deficiency, JAK2, protein C or protein S deficiency (can

be genetic or acquired)

Mechanical

Head trauma (1%-3%)

Compressive lesions of venous sinus (meningioma)

Neurosurgical procedures

Dural arteriovenous fistula

Jugular vein catheterizations (1%-2%

iatrogenic)

Percentages indicate presence of factors among those with CVT; may be >100% because many patients may have >1 predisposing condition.

CVT indicates cerebral venous thrombosis.

hemorrhagic lesions at baseline or superior sagittal sinus

adjudicated).³² A recent retrospective study of VTE

involvement, and craniectomy.^27,28 Dural arteriovenous

recurrence (including CVT) reported rates of 5.68 per

fistula is a reported complication of CVT, but CVT can

100 patient-years, more than half of which were CVT.⁸

also be a sequela of dural arteriovenous fistula. A large

A study from Norway found that individuals with CVT

retrospective series of 1218 individuals with CVT found

(n=654; median age, 41 years; 67% women) compared

a prevalence of new dural arteriovenous fistula of 2.4%

with general population age- and sex-matched control

at a median follow-up of 8 months (interquartile range,

subjects were at increased risk of recurrent VTE, isch-

5-23 months), although no systematic timing or neuro-

emic stroke, major bleeding, and mortality at 10 years.

imaging protocol was included in the study.²⁹ A prospec-

Risks of recurrent VTE were higher in younger individu-

tive study with systematic imaging collection at 6 months

als (age, 18-54 years) with CVT compared with the

after CVT found no dural arteriovenous fistula.³⁰

general population, whereas risks of ischemic stroke,

The incidence of recurrent venous thromboembolism

major bleeding, and mortality (risk difference, 11.5% for

(VTE) after CVT ranges from 1% to 4% per year, with

women ≥55 years of age and 5.8% for men ≥55 years)

rates of CVT recurrence generally reported as <1% to

were highest in older patients.³³

2% per year.^6,31 A higher risk of recurrence has been

reported in individuals with severe thrombophilia (includ-

ing malignancy), those with a history of VTE, individuals

BRAIN AND VASCULAR IMAGING FOR THE

with events without identified precipitants, and, incon-

DIAGNOSIS OF CVT

sistently, male individuals.^6,31 A secondary analysis of

ACTION-CVT (Anticoagulation in the Treatment of CVT)

Conventional computed tomography (CT) or magnetic

showed a VTE recurrence of 6.4% (2.5% for CVT recur-

resonance imaging (MRI) is often the first test obtained

rent alone although brain images were not centrally

in patients with nonspecific acute presentations and may

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Saposnik et al

Diagnosis and Management of Cerebral Venous Thrombosis

show signs that increase suspicion for CVT. For exam-

and basal ganglia hemorrhages are uncommon.⁴ The

ple, CVT on CT or MRI may be suspected by (1) direct

cashew nut sign, a juxtacortical C-shaped hyperdensity,

visualization of the thrombus, (2) the absence of venous

is reported to have a high specificity for CVT but has

filling, and (3) imaging of the consequences of venous

low sensitivity (Figure 2A).³⁶ Bilateral or multifocal hem-

obstruction at the tissue level (venous infarction, edema

orrhages also occur frequently (Figure 2F). In a recent

and hemorrhagic transformation, intracranial hyperten-

meta-analysis of 27 publications with 2812 cases, CT

sion and hydrocephalus) and at the vascular level (dilated

had a sensitivity of 0.79 (95% CI, 0.76-0.82) and speci-

veins).^1,34 Common challenges of brain imaging are sum-

ficity of 0.90 (95% CI, 0.89- 0.91),³⁵ lower than previ-

marized in Supplemental Table 2.

ously reported in the 2011 American Heart Association

Direct imaging of thrombus is possible on CT, espe-

statement.¹

cially with the increased use of thin-slice CT (Fig-

Thrombi can also be directly observed on conven-

ure 2A-2D).^1,35 On noncontrast CT this is observed as

tional MRI sequences (Figure 3).^1,37 Because the evolu-

hyperattenuation due to increase of hemoglobin and

tion of a thrombus on MRI is dynamic, changes in the

red blood cells within the thrombus (dense vessel sign;

signal intensity of the thrombus over time are similar

Figure 2B-2E). The traditional cord or string sign, a ser-

to that of a hematoma. As the thrombus ages, oxyhe-

piginous or linear hyperdensity within a vein, or dense

moglobin is converted to deoxyhemoglobin and methe-

triangle sign can be present up to 14 days after onset

moglobin, leading to changes in signal characteristics

of symptoms (Figure 2E). Indirect signs that raise the

on the T1 and T2 sequences. In these early stages, it

suspicion on noncontrast CT (and MRI) include areas

is difficult to diagnose thrombosis because T2 may

of hypodensity not conforming to typical wedge-shaped

be isointense or hypointense, mimicking a normal flow

infarctions or that are not limited to specific arte-

void of a venous sinus. Similarly, time-of-flight magnetic

rial territories or sparing the overlying cortex. Bilateral

resonance venography (MRV) is susceptible to misdiag-

hypodensities may occur when the sagittal sinus or deep

nosis because absent flow is not always corroborated

cerebral veins are involved. Hemorrhages are present

on T1//T2 sequences (Supplemental Table 2). Conse-

in up to 40% of CVT and include areas of hemorrhagic

quently, it is often helpful to corroborate findings with

transformation within regions of hypodensity or frank

gradient-recalled echo, susceptibility-weighted imaging

intracerebral hemorrhage associated with subarachnoid

sequences, or contrast-enhanced MRV.^34,37 Thrombosed

or subdural hemorrhages.^2,4,16 Isolated subarachnoid

blood creates a blooming artifact on gradient-recalled

Figure 2. Typical findings of cerebral venous thrombosis on noncontrast computed tomography.

A, Left-sided juxtacortical C-shaped hemorrhages. B, Transverse sinus thrombosis. C, Straight sinus thrombosis. D, Internal cerebral vein

thrombosis (arrow) and left thalamic hypodensity (*). E, Cord sign (arrow) and hyperdense sagittal sinus thrombosis (*). F, Multiple small

hemorrhages in same patient as in E. Arrows indicate cord sign.

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Diagnosis and Management of Cerebral Venous Thrombosis

Figure 3. Typical findings of cerebral venous thrombosis on magnetic resonance imaging.

A, Bilateral thalamic hyperintensity (arrows) on fluid-attenuated inversion recovery (FLAIR) in a patient with deep cerebral vein thrombosis. B,

Susceptibility-weighted imaging shows hypointensity of the straight sinus (arrow), vein of Galen, and internal cerebral veins. C, Venous infarction

due to transverse sinus thrombosis with heterogeneous FLAIR hyperintensity (arrow). D, Bilateral FLAIR hyperintensities (arrows) with mass

effect in a patient with superior sagittal sinus thrombosis (arrow), shown in E on a contrast-enhanced T1 sequence and in F absent venous filling

defect (arrow) with phase-contrast magnetic resonance venography.

echo or susceptibility-weighted imaging sequences that

from arachnoid granulations. Several small to moderately

is especially useful in the identification of inconspicuous

sized studies have demonstrated a high sensitivity and

findings (Figure 3B) such as thrombosed cortical veins,

specificity of CTV compared with digital subtraction angi-

where they have a sensitivity and specificity approaching

ography or a consensus reading of other imaging modali-

100%.^34,37 Advanced MRI techniques such as T1-based

ties. Compared with MRI, CTV has a lower sensitivity for

black-blood imaging (in which signal from flowing blood

cortical vein thrombosis.³⁷

is suppressed) are promising. MRI is more sensitive than

MRV (Figure 3) can be performed without contrast,

CT in the detection of parenchymal brain lesions second-

with time-of-flight (TOF) or phase-contrast techniques,

ary to venous occlusion such as venous infarctions (Fig-

or with a contrast-enhanced technique (Figure 3E and

ure 3A, 3C, and 3D).³⁸ Radiologically, these lesions cross

3F). The use of gadolinium with contrast-enhanced tech-

arterial vascular territories and may be bilateral.

nique allows direct assessment of luminal filling and

A meta-analysis of 21 studies with 1773 patients

increases the sensitivity of the detection of thrombus

with CVT showed conventional MRI sequences to have a

within the smaller veins.^1,37 Both TOF and phase-contrast

sensitivity of 0.82 (95% CI, 0.78-0.85) and specificity of

MRV techniques can be prone to artifact secondary to

0.92 (95% CI, 0.91-0.94).³⁵

complex flow. TOF is, however, still commonly used and is

especially useful in situations that may preclude gadolin-

ium administration such as in pregnant or breastfeeding

CONFIRMING THE DIAGNOSIS OF CVT

patients or in patients with severe renal failure. Compared

CT venography and MRV are the optimal tests to con-

with 3-dimensional TOF, 2-dimensional TOF has higher

firm a diagnosis of CVT. Digital subtraction angiogra-

sensitivity in the setting of slow flow. Phase-contrast MRI

phy is typically used only when invasive treatments are

is used less frequently because defining the velocity of

considered.¹

the encoding parameter is not only difficult but opera-

CT venography allows clear depiction of the superfi-

tor dependent and requires longer acquisition times.

cial and deep cerebral venous system. Thrombi present

Contrast-enhanced MRV has a sensitivity and specific-

as filling defects (“empty delta sign” referred to the supe-

ity comparable to that of CTV but allows better charac-

rior sagittal sinus) and can usually be easily distinguished

terization between the low-flow state and hypoplastic

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Saposnik et al

Diagnosis and Management of Cerebral Venous Thrombosis

sinus (flow gaps).³⁹ Contrast-enhanced techniques and

of 6 months.²⁵ There was no requirement for lead-in par-

gradient-recalled echo or susceptibility-weighted imag-

enteral anticoagulation. The trial excluded individuals with

ing are recommended for diagnosing cortical vein throm-

pregnancy and antiphospholipid antibody syndrome. Nine-

bosis (new evidence since the 2011 American Heart

teen of 26 individuals in the rivaroxaban group received

Association statement).^1,34,37

≤4 days of lead-in parenteral anticoagulation.

There were no safety concerns related to early initia-

tion of DOAC. By 6 months, there were 1 recurrent CVT

THERAPEUTIC ADVANCES IN THE

(3.8% [95% CI, 0.1%-19.6%]), 1 symptomatic intrace-

MANAGEMENT OF CVT

rebral hemorrhage (3.8% [95% CI, 0.1%-19.6%]), and 2

clinically relevant nonmajor bleeding events (7.7% [95%

Oral Anticoagulation

CI, 0.9%-25.1%]) in the rivaroxaban group and no VTE

The objectives of anticoagulation therapy in CVT are

recurrence or bleeding events in the control group.

to prevent thrombus growth, to facilitate recanalization,

ACTION-CVT, a large retrospective international study,

and to prevent recurrent VTE events. Previous Ameri-

compared events in 845 consecutive individuals with CVT

can Heart Association/American Stroke Association

who were prescribed VKA versus DOAC as part of their

and European guidelines for the management of CVT

routine clinical care between 2015 and 2020.⁸ DOACs

recommend the initial use of low-molecular-weight

used included apixaban (67%), rivaroxaban (18%), and

heparin (LMWH) over unfractionated heparin followed

dabigatran (14%) or multiple DOACs (3%). Individuals

by transition to oral vitamin K antagonists (VKAs) for 3

with malignancy, those with antiphospholipid antibody

to 12 months in the context of transient risk factors or

syndrome, and those who were pregnant were excluded.

indefinitely in the context of chronic major risk factors

The study found no significant difference in rates of

for thrombosis or recurrent VTE (Figure 4).^1,16,40 LMWH

recurrent VTE (adjusted hazard ratio, 0.94 [95% CI, 0.15-

is favored in the acute treatment of CVT given the more

1.73]), and there was a reduced risk of major hemorrhage

practical administration, more predictable anticoagulation

(adjusted hazard ratio, 0.35 [95% CI, 0.15-0.82]), driven

effect, lower risk of thrombocytopenia, and trends toward

primarily by a lower risk of intracerebral hemorrhage, in

better outcomes in meta-analyses that do not meet the

the DOAC group.⁸ There were no differences in recanali-

threshold for statistical significance.^41,42 The presence of

zation rates between groups in either study.^8,47

venous hemorrhage does not constitute a contraindica-

A recent systematic review summarizing 3 randomized

tion for anticoagulation.^1,16,43 Whether degree of venous

trials and 16 observational studies comparing DOACs

recanalization should inform duration of anticoagulation

with VKAs found similar rates with both treatments of

remains an area of uncertainty.^44-46

recurrent VTE, major hemorrhage, and complete recana-

An emerging body of evidence suggests that direct

lization (42.9% versus 42.3%; relative risk, 0.98 [95% CI,

oral anticoagulants (DOACs), which have demonstrated

0.87-1.11]).⁴⁸

efficacy and safety compared with VKA for individuals

From the current available evidence, it is reasonable

with deep venous thrombosis and pulmonary embolism,

to transition to DOAC or VKA after a period of lead-in

may also be a reasonable choice for oral anticoagulation

parenteral anticoagulation, but whether 5 to 15 days is

in selected individuals with CVT.

a safer or more effective strategy than shorter periods is

RE-SPECT CVT (A Clinical Trial Comparing Efficacy

not known.⁴⁷

and Safety of Dabigatran Etexilate With Warfarin in Patients

Additional clinical trials and prospective observational

With Cerebral Venous and Dural Sinus Thrombosis) was an

studies are ongoing (ClinicalTrials.gov NCT03178864,

international prospective clinical trial that randomized 120

NCT04660747). Persistent areas of controversy include

individuals with CVT 1:1 to warfarin VKA with target inter-

timing of initiation with or without lead-in heparin, whether

national normalized ratio of 2.0 to 3.0 or dabigatran 150

acute VTE dosing is initially required, and optimal can-

mg twice daily for 6 months after 5 to 15 days of lead-in

didates for DOAC therapy. DOACs are not suitable in

parenteral anticoagulation.⁴⁷ The trial excluded individuals

women who are pregnant (both DOAC and warfarin are

with malignancy, central nervous system infection, trauma,

contraindicated; only LMWH is recommended) or breast-

and pregnancy. There were no recurrent VTEs in either

feeding (DOACs are contraindicated; Figure 4). DOACs

group, with 1 (1.7% [95% CI, 0.0%-8.9%]) major hemor-

have also been associated with higher risks of recurrent

rhage (gastrointestinal bleeding) in the dabigatran group

thromboembolic events compared with warfarin in indi-

and 2 (3.3% [95% CI, 0.4%-11.5%], both intracerebral

viduals with antiphospholipid antibody syndrome.^49,50 For

hemorrhages) in the warfarin group.

patients with cancer, DOACs were at least noninferior

SECRET (Study of Rivaroxaban in Cerebral Venous

to LMWH in the prevention of VTE. There is limited evi-

Thrombosis) was a phase II trial that randomized 53 par-

dence of the role of antiplatelet agents after discontinu-

ticipants with CVT 1:1 to rivaroxaban 20 mg daily versus

ation of oral anticoagulation in CVT. Studies focused on

standard-of-care anticoagulation (warfarin; target interna-

secondary prevention of VTE showed that aspirin was

tional normalized ratio, 2.0-3.0] or LMWH) for a minimum

more effective than placebo (hazard ratio, 0.68 [95% CI,

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Diagnosis and Management of Cerebral Venous Thrombosis

Figure 4. Proposed algorithm for the management of CVT.

This figure summarizes the suggested approach for the diagnosis and management of CVT. CT indicates computed tomography; CTV, computed

tomographic venography; CVT, cerebral venous thrombosis; LMWH, low-molecular-weight heparin; MRI, magnetic resonance imaging; MRV,

magnetic resonance venography; OAC, oral anticoagulant; and VTE, venous thromboembolism.

0.51-0.90]; P=0.008).⁵¹ Compared with all comers with

population, is uncertain.⁵² Several studies in the past

VTE, those with CVT are younger and thus would have

decade that reported the use of mechanical thrombec-

a longer lifetime exposure to aspirin. In addition, the CVT

tomy (either balloon assisted or through aspiration or

literature describing longer-term recurrence risk of VTE

vacuum aspiration systems), intrasinus thrombolysis,

is less robust.^31,33 Thus, potential benefits should be care-

combination of mechanical thrombectomy and intra-

fully considered along with individual patient characteris-

sinus thrombolysis, intra-arterial thrombolysis, and intra-

tics in shared decision-making.

sinus stenting provide controversial evidence on safety

and complication rates.^43,53 The multicenter, randomized

clinical TO-ACT trial (Thrombolysis or Anticoagulation for

Reperfusion Therapies

CVT) showed that patients with severe CVT did not ben-

Endovascular treatment (EVT) options for the manage-

efit clinically from EVT compared with the patients receiv-

ment of CVT could theoretically offer faster recanaliza-

ing standard anticoagulation therapy.⁵⁴ Larger studies

tion, although any association with a more favorable

and meta-analyses showed that EVT is associated with

outcome in medical therapy, particularly in an unselected

higher mortality and no evidence of benefit with EVT.^55-58

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Diagnosis and Management of Cerebral Venous Thrombosis

Currently, EVT is used as a rescue treatment for

there is deterioration in level of consciousness, more inva-

patients who are experiencing clinical deterioration

sive procedures should be considered and may poten-

or failed or have contraindications to standard therapy

tially be lifesaving (Figure 4). Anticoagulation in the acute

(Figure 4).⁵³ In a systematic review including 10 studies

phase is more controversial in premature and term neo-

comprising 339 patients who underwent EVT for CVT,

nates but is reasonable because there is no evidence of

the authors found a complete and partial postoperative

posttreatment hemorrhage, whereas lack of anticoagula-

recanalization in 90.0% of patients, increasing to 95.2%

tion may lead to thrombus propagation.^65,66 CVT in chil-

during the follow-up.⁵⁹ The complication rate was 10.3%.

dren carries a mortality rate of 3%, and recurrent venous

There is no current evidence to determine which EVT

thrombosis occurs in ≈6%, usually associated with no

technique (eg, stent retriever, microcatheters, aspiration

administration of anticoagulation and lack of venous

catheters, aspiration pump systems) is superior to other

recanalization.⁶⁴ Since the prior scientific statement,¹

therapeutic strategies.

there have been randomized trials on duration of antico-

agulation and the use of DOACs.⁶⁷ In individuals 4 months

to 20.9 years of age, the Kids-DOTT trial (Multicenter

Decompressive Craniectomy

Evaluation of the Duration of Therapy for Thrombosis in

The evidence on decompressive craniectomy for CVT

Children) compared 6 weeks with 3 months of anticoagu-

remains unchanged since the previous American Heart

lation for provoked VTE (including 59/417; 25% patients

Association statement.¹ It should be offered to patients

with CVT). Six weeks of anticoagulation was noninferior

with acute severe CVT and parenchymal lesions with

for recurrent VTE and bleeding events.⁶⁷

impending herniation as a lifesaving therapeutic approach

In the EINSTEIN-Jr trial (Oral Rivaroxaban in Children

(Figure 4).⁶⁰ Factors associated with poorer outcomes

With Venous Thrombosis), after initial heparinization, 114

included age >50 years, midline shift >10 mm, and total

children with confirmed CVT were randomized (2:1) to 3

effacement of basal cisterns.⁶¹ There are no randomized

months of rivaroxaban or standard anticoagulation (con-

controlled trials of this surgical approach in the litera-

tinuing heparin or switching to oral VKAs).⁶⁸ The primary

ture. A systematic review and meta-analysis including 51

efficacy outcome was symptomatic recurrent VTE, and

studies comprising 483 patients with CVT showed that

the principal safety outcome was major or clinically rel-

surgery within 48 hours of admission may decrease mor-

evant nonmajor bleeding. With 100% follow-up, none of

tality (odds ratio [OR], 0.26 [95% CI, 0.10-0.69]) and

the 73 children treated with rivaroxaban compared with 1

result in improved functional outcomes.⁶²

of the 41 children treated with standard anticoagulation

had symptomatic recurrent VTE (absolute difference,

2.4% [95% CI, -2.6% to 13.5%]). Five patients on rivar-

CVT IN SPECIAL POPULATIONS

oxaban had nonmajor and noncerebral bleeding, whereas

1 patient on standard anticoagulation had a major sub-

Pediatric Population

dural bleed. Complete or partial recanalization occurred

CVT is more common in neonates (6.4/100 000) than

in 18 (25%) and 39 (53%) patients on rivaroxaban and

in children and adolescents.⁶³ The key to successful

6 (15%) and 24 (59%) patients on standard antico-

management is to consider the diagnosis early in acute

agulation. No children died by the end of the 3-month

presentations with headache, seizures, focal neurological

study treatment period. Focal neurological deficits were

deficits, or coma and in typical situations such as sepsis

observed in 5 (6.8%) and 3 (7.3%) children in the rivar-

(including mastoiditis, Lemierre syndrome, COVID-19,

oxaban and standard anticoagulation group, respectively,

and meningitis), head trauma (including abuse), hypoxia,

at the end of the study. However, other long-term stud-

and dehydration. Awareness is especially important in

ies suggest that despite treatment 1 in 4 children may

children with preexisting conditions (congenital heart dis-

develop late epilepsy,⁶⁹ infantile spasms after neonatal

ease and its surgical treatment, cancer and its treatment,

CVT, cognitive impairment, or intracranial hypertension.⁷⁰

anemia due to iron deficiency or hemoglobinopathies,

and inflammatory conditions, eg, nephrotic syndrome

CVT During Pregnancy and Puerperium

and inflammatory bowel disease). Emergency imaging to

diagnose or exclude dural or cortical venous thrombosis

Pregnancy induces changes in the coagulation system

with or without parenchymal involvement or hemorrhage

that persist into the puerperium and result in a hyper-

typically requires anesthesia. Initial blood work may reveal

coagulable state, increasing the risk of CVT. Incidence

low platelets associated with platelet factor 4 mutations

estimates during pregnancy and the puerperium range

or high platelets and high hemoglobin associated with

from 1 in 2500 deliveries to 1 in 10 000 deliveries in

JAK2 mutations, as well as indices of iron deficiency with

Western countries, and ORs range from 1.3 to 13.0. The

or without anemia.^63,64

greatest risk periods for CVT include the third trimester

The management of acute CVT in children typically

and the first 6 postpartum weeks. Approximately 80%

involves LMWH or unfractionated heparin. As for adults, if

of pregnancy-related CVT cases occur after delivery.¹² A

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Diagnosis and Management of Cerebral Venous Thrombosis

case-control study found that the risk is increased only in

poor prognosis, with mortality rates ranging from 39% to

the puerperium (OR, 10.6 [95% CI, 5.6-20.0]), whereas

61% in initial cohort studies.^80,82,83 A study on the global

there was no statistically significant increased risk of CVT

impact of COVID-19 that included 2313 CVT admissions

during pregnancy (OR, 1.2 [95% CI, 0.6-2.3]).¹⁰ Cesar-

across 1 prepandemic year (2019) and 1 pandemic year

ean delivery appears to be associated with a higher risk

(2020) found 26 cases of VITT, resulting in 6 deaths. A

after adjustment for age, vascular risk factors, presence

diagnosis of COVID-19 infection was present in 7.6% of

of infections, hospital type, and location (OR, 3.10 [95%

all CVT admissions.¹⁹

CI, 2.26-4.24]).¹⁰ Overall, studies published since the

A pharmacovigilance study comprising

>1.7 mil-

prior scientific statement¹ have found that the prognosis

lion adverse reactions showed a disproportionately

for women with pregnancy-related CVT is better than or

lower incident risk of CVT after vaccination with mRNA

the same as that for patients with CVT in general.⁷¹

SARS-CoV-2 vaccines compared with adenovirus-based

VKAs, including warfarin, are associated with fetal

SARS-CoV-2 vaccines (1-5/10 000 for BNT162b2 and

embryopathy and bleeding in the fetus and neonate and

mRNA-1273 versus 13/10 000 for ChAdOx1 nCoV-19

thus are contraindicated in pregnancy. Therefore, antico-

vaccine).⁸⁴ In addition, there is no evidence of VITT after

agulation for CVT during pregnancy and early in the puer-

mRNA vaccines.^76,84

perium consists of LMWH in the majority of women.^12,72,73

In cases of suspected VITT, laboratory testing for

There is limited evidence on endovascular therapies in

platelet factor 4 antibodies is recommended. Despite

this population. As in nonpregnant women, thrombolysis

the lack of evidence, given the similarity to autoimmune

and thrombectomy are reserved for patients with neu-

heparin-induced thrombocytopenia, avoidance of hepa-

rological deterioration or propagation of the thrombus

rin products, intravenous immunoglobulin 1 g/kg body

despite medical therapy (Figure 4).

weight daily for 2 days, and administration of steroids

have been advised. Platelet transfusions are not rec-

ommended.⁸⁵ Nonheparin parenteral anticoagulants

Future Pregnancies and Recurrence

(argatroban, fondaparinux) are typically used first, with

Women with a history of VTE appear to have an increased

transition to an oral anticoagulant (ie, DOAC) once there

risk of thrombotic events (ie, deep venous thrombosis,

is full platelet count recovery.⁸⁰

pulmonary embolism) in future pregnancies.⁶⁴ A system-

atic review comprising 17 studies and 393 pregnan-

cies found a recurrence rate of 8 per 1000 pregnancies

KEY POINTS FOR CLINICAL PRACTICE

(95% CI, 3-22). The rate of noncerebral VTEs was 22

• CVT requires a high level of suspicion among patients

per 1000 pregnancies (95% CI, 11-43).⁷⁴ There was a

presenting with common symptoms and known pre-

trend toward a lower rate of recurrent thrombotic events

disposing conditions (pregnancy, puerperium, use of

in women who used antithrombotic prophylaxis.⁷⁴

oral contraceptives, thrombophilia) or demographic

According to the available evidence, CVT is not a

factors (young women).

contraindication for future pregnancies.^12,72,75 Consider-

• New predisposing conditions (obesity, COVID-19,

ing the additional risk that pregnancy confers to women

vaccine-induced thrombocytopenia)^2,15,18 were identi-

fied since our previous report.¹ (New)

with a history of CVT, prophylaxis with LMWH during

• MRI/MRV is the recommended noninvasive study of

future pregnancies and the postpartum period is prob-

the cerebral venous system to confirm the diagnosis.

ably beneficial.⁷⁵

CT/CTV is a reasonable alternative in centers with

limited resources or if the pretest probability is low.

• Contrast-enhanced MRV, gradient-recalled echo, or

VITT and CVT

susceptibility-weighted imaging sequences are the

In 2021, reports from Europe and the United States

recommended techniques for the diagnosis of corti-

described thrombocytopenia and CVT after vaccination

cal venous thrombosis. (New)

with the ChAdOx1 nCoV-19 vaccine (AstraZeneca) and

• The mainstream initial treatment of CVT includes par-

the Ad26.COV2.S adenovirus-based SARS-CoV-2 vac-

enteral heparin followed by transition to oral VKAs for

cine (Janssen).^76-78 The age range of affected patients

3 to 12 months, depending on the underlying cause,

or indefinitely in the presence of thrombophilia or

was 18 to 77 years; most were women. Symptoms began

recurrent VTE (Figure 4).

5 to 24 days after vaccination.⁷⁶ Headache was the most

• DOACs appear to be a safe and effective alternative

common presenting feature. All patients had throm-

option to VKAs according to open-label retrospective

bocytopenia. In the United Kingdom, 23 patients with

and prospective randomized studies. (New)

antibodies to platelet factor 4 after ChAdOx1 nCoV-19

• The strategy of identifying venous recanalization in

vaccination were described. It is believed that DNA from

subsequent CTV or MRV to guide the duration of anti-

the adenovirus-infected cells bonded to platelet factor

coagulation remains uncertain. (New)

4 and triggered the production of autoantibodies.^79,80

• Given the lack of controlled studies (and poorer out-

Although CVT in VITT is a rare condition,⁸¹ it carries a

comes in meta-analyses), endovascular therapies

Stroke. 2024;55:e00-e00. DOI: 10.1161/STR.0000000000000456

TBD 2024 e9

Saposnik et al

Diagnosis and Management of Cerebral Venous Thrombosis

are reserved for patients with evidence of thrombus

ARTICLE INFORMATION

propagation, for individuals with neurological dete-

The American Heart Association makes every effort to avoid any actual or poten-

rioration despite medical therapy, or for those with

tial conflicts of interest that may arise as a result of an outside relationship or a

contraindications to anticoagulation (Figure 4).

personal, professional, or business interest of a member of the writing panel. Spe-

cifically, all members of the writing group are required to complete and submit a

(New)

Disclosure Questionnaire showing all such relationships that might be perceived

• Despite the low level of evidence, decompressive

as real or potential conflicts of interest.

surgery is a lifesaving procedure that may result in

This statement was approved by the American Heart Association Science Ad-

improved functional outcomes among patients with

visory and Coordinating Committee on October 11, 2023, and the American Heart

Association Executive Committee on December 4, 2023. A copy of the document

advanced clinical signs of herniation. (New)

is available at https://professional.heart.org/statements by using either “Search

• For women with CVT during pregnancy, LMWH in full

for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional

anticoagulant doses should be continued throughout

reprints, call 215-356-2721 or email Meredith.Edelman@wolterskluwer.com

pregnancy, and LMWH or VKA with a target interna-

The American Heart Association requests that this document be cited as

tional normalized ratio of 2.0 to 3.0 should be con-

follows: Saposnik G, Bushnell C, Coutinho JM, Field TS, Furie KL, Galadanci N,

Kam W, Kirkham FC, McNair ND, Singhal AB, Thijs V, Yang VXD; on behalf of the

tinued for at least 6 weeks postpartum (for a total

American Heart Association Stroke Council; Council on Cardiopulmonary, Criti-

minimum duration of therapy of 3 months).

cal Care, Perioperative and Resuscitation; Council on Cardiovascular and Stroke

• It is reasonable to advise women with a history of

Nursing; and Council on Hypertension. Diagnosis and management of cerebral

CVT that future pregnancy is not contraindicated.

venous thrombosis: a scientific statement from the American Heart Association.

Stroke. 2024;55:e•••-e•••. doi: 10.1161/STR.0000000000000456

Prophylaxis with LMWH during future pregnancies

The expert peer review of AHA-commissioned documents (eg, scientific

and the postpartum period is usually recommended.

statements, clinical practice guidelines, systematic reviews) is conducted by the

• CVT in the pediatric population is more common in

AHA Office of Science Operations. For more on AHA statements and guidelines

neonates than children, usually among those exposed

development, visit https://professional.heart.org/statements. Select the “Guide-

to infections, dehydration, iron deficiency, anemia, or

lines & Statements” drop-down menu, then click “Publication Development.”

Permissions: Multiple copies, modification, alteration, enhancement, and dis-

head trauma. Parenteral anticoagulation is also the

tribution of this document are not permitted without the express permission of the

first-line treatment, followed by LMWH, VKA, or rivar-

American Heart Association. Instructions for obtaining permission are located at

oxaban for at least 6 weeks.

• VITT and CVT may occur (rarely) days or a few weeks

Form” appears in the second paragraph (https://www.heart.org/en/about-us/

statements-and-policies/copyright-request-form).

after an individual receives adenovirus-based SARS-

CoV-2 vaccines, usually presenting with new onset

Acknowledgments

of headaches and thrombocytopenia; it requires the

The authors appreciate the support of Dr Gokce H. Majernik (vascular fellow at

expert management of a hematologist and multidisci-

the London Health Sciences Center, London, Ontario, Canada) for reviewing the

plinary team. (New)

section on endovascular therapy in CVT.

Disclosures

Writing Group Disclosures

Writing

Other

Speakers’

Consultant/

group

research

bureau/

Expert

Ownership

advisory

member

Employment

Research grant

support

honoraria

witness

interest

board

Other

Gustavo

St Michael’s Hos-

None

Saposnik

pital, University of

Toronto (Canada)

Cheryl

Wake Forest

None

Bushnell

School of

Medicine

Jonathan

Amsterdam

Bayer*; AstraZeneca*; Dutch

None

TrianecT*

None

M. Coutinho

UMC, University

Heart Foundation (nonprofit

of Amsterdam

organization)*; Dutch Thrombosis

(Netherlands)

Foundation (nonprofit

organization)*; ZonMw (nonprofit

government organization)*; All fees

paid to his employer for all.

Thalia S.

University of

Canadian Institutes of Health

None

Canadian

DESTINE

None

Field

British Columbia

Research (research grant to her

Medical

Health*

Centre for Brain

institution)†; Heart and Stroke

Protective

Health (Canada)

Foundation of Canada (research

Association*

grant to her institution)†;

Bayer Canada (in-kind study

medication)†

Karen L

Rhode Island

None

Furie

Hospital

(Continued )

e10 TBD 2024

Stroke. 2024;55:e00-e00. DOI: 10.1161/STR.0000000000000456

Saposnik et al

Diagnosis and Management of Cerebral Venous Thrombosis

Writing Group Disclosures Continued

Writing

Other

Speakers’

Consultant/

group

research

bureau/

Expert

Ownership

advisory

member

Employment

Research grant

support

honoraria

witness

interest

board

Other

Najibah

University of

None

Galadanci

Alabama at

Birmingham

Wayneho

Duke University

None

Kam

Hospital; UNC

Health Rex

Comprehensive

Stroke Center

Fenella J.

UCL GOSH

Action Medical Research (RCT

None

Pfizer†

UCL

Kirkham

Institute of Child

of Montelukast in SCD with

(professor

Health (United

processing speed end point)†

of pediatric

Kingdom)

neurology)†

Norma D.

Retired Nursing

None

McNair

Aneesh B.

Massachusetts

MGH Fireman Vascular Center

None

MedicoLegal

None

Singhal

General Hospital

(SPARK Award)*

expert

witness*

Vincent

Florey Neurology

None

Boehringer

None

Thijs

(Australia)

Ingelheim*

Victor X. D.

Sunnybrook

None

Yang

Health Sciences

Center (Canada)

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the

Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person

receives $5000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the

entity, or owns $5000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.

*Modest.

†Significant.

Reviewer Disclosures

Other

Speakers’

Consultant/

Research

research

bureau/

Expert

Ownership

advisory

Reviewer

Employment

grant

support

honoraria

witness

interest

board

Other

Ekaterina

University of Alabama

None

Bakradze

at Birmingham

José Ferro

Faculdade

None

de Medicina,

Universidade de

Lisboa (Portugal)

Matthew

Massachusetts

None

Frosch

General Hospital

Hans-

Vivantes Klinikum

None

Medical guidelines (I am member of

Christian

im Friedrichshain

the writing group for guidelines for

Koennecke

(Germany)

cerebral venous thrombosis of the

Deutsche Gesellschaft für Neurologie

[German Neurological Society])*

Thanh

Boston University

None

Idorsia*

None

Nguyen

Chobanian and

Avedisian School of

Medicine

Brian Silver

UMass Memorial

None

Medical Center

Kori

Massachusetts

None

Zachrison

General Hospital

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Ques-

tionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $5000 or more during any

12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $5000 or more of

the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.

*Modest.

Stroke. 2024;55:e00-e00. DOI: 10.1161/STR.0000000000000456

TBD 2024 e11

Saposnik et al

Diagnosis and Management of Cerebral Venous Thrombosis

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e14 TBD 2024

Stroke. 2024;55:e00-e00. DOI: 10.1161/STR.0000000000000456

Core Curriculum in Nephrology

Urinary Tract Infections: Core Curriculum

2024

Hawra Al Lawati, Barbra M. Blair, and Jeffrey Larnard

Urinary tract infections (UTIs) are some of the most commonly encountered infections in clinical

Complete author and article

information provided at end

practice. Accurate diagnosis and evidence-based treatment of UTIs will lead to better clinical care for

of article.

many patients and limit unnecessary antibiotic use. Urinalysis and urine cultures are helpful tools in the

diagnosis of UTIs; however, it is important to recognize their limitations. Differentiating between

Am J Kidney Dis. 83(1):90-

asymptomatic bacteriuria (ASB) and true UTI is important because antibiotics are unnecessary in most

100. Published online

October 30, 2023.

nonpregnant patients with ASB and can even potentially cause harm if prescribed. Choice and

duration of antibiotics varies across the spectrum of UTI syndromes such as acute uncomplicated

doi: 10.1053/

j.ajkd.2023.08.009

cystitis, pyelonephritis, prostatitis, and catheter-associated UTIs. The treatment approach also de-

pends on patients’ degree of immunosuppression and their genitourinary anatomy. Therefore, patients

with urological obstruction or kidney transplants may require a specialized and multidisciplinary

Kidney Foundation, Inc.

management approach. For individuals prone to frequent UTIs, some preventative measures can be

utilized, yet there is often not a “one size fits all” approach.

sensation during urination with urinary fre-

FEATURE EDITOR

Introduction

quency and discomfort in her lower abdomen.

Melanie Hoenig

Urinary tract infection (UTI) is a broad term

She recalls having the same symptoms a year

that encompasses a spectrum of infectious

ago, which was the only other time she was

ADVISORY BOARD

syndromes that affect the urinary tract any-

treated for a UTI. She is otherwise healthy and

Ursula C. Brewster

Michael J. Choi

where from the urethra to the kidneys. UTIs

takes no medications. Her last menstrual period

Biff F. Palmer

are some of the most common infections, and

was 2 weeks ago.

Bessie Young

it is reported that 50%-60% of women have at

least 1

UTI in their lifetime. The usual

Question 1: What is the best next step in

The Core Curriculum

mechanism of infection is bacteria colonizing

the management of this patient?

aims to give trainees

the urethra or periurethral space migrating

(a) Ask her to submit a urine sample for uri-

in nephrology a

strong knowledge

into the bladder and causing an inflammatory

nalysis and urine culture and recommend

base in core topics in

antibiotics pending culture results.

response. The bacteria that typically cause this

the specialty by

(b) Prescribe ciprofloxacin 500 mg twice daily

are from the gastrointestinal (GI) tract and are

providing an over-

for 7 days.

collectively called Enterobacterales; examples

view of the topic and

include Escherichia coli, Klebsiella pneumoniae, and

citing key references,

for 5 days.

including the founda-

Proteus mirabilis. Another possible way of

(d) Prescribe amoxicillin 875 mg twice daily for

tional literature that

developing UTIs is bacteria in the bloodstream

5 days.

led to current clinical

migrating to the kidneys or bladder, but this is

(e) Prescribe cefpodoxime 100 mg twice daily

approaches.

very rare. The risk factors for UTIs include

for 5 days.

female sex, recent sexual intercourse, diabetes

For the answer to this question, see the

mellitus, and structural or functional uro-

following text.

logical abnormalities. Diagnosis and manage-

ment depend on patient factors and the extent

of disease. In this installment of AJKD’s Core

Diagnosis and Testing

Curriculum in Nephrology, we provide a re-

view of the clinical presentation, diagnosis,

Acute uncomplicated cystitis (also known as

and evidence-based management of common

“simple cystitis”) is a type of UTI, specif-

and important UTI syndromes such as cystitis,

ically an infection of the bladder in an

pyelonephritis, asymptomatic bacteriuria,

otherwise immunocompetent host with

prostatitis, catheter associated UTIs, and

normal urinary tract anatomy. The classic

recurrent UTIs.

symptoms are dysuria, urinary frequency,

urinary urgency, or suprapubic pain in the

absence of systemic illness (eg, fever, rigors, or

Acute Uncomplicated Cystitis

vomiting) or upper urinary tract involve-

Case 1: A 27-year-old woman calls her phy-

ment (eg, flank pain or costovertebral angle

sician’s office reporting 3 days of a burning

tenderness). “Complicated UTI” is a broad

AJKD Vol 83 | Iss 1 | January 2024

Al Lawati et al

term that has been traditionally used to lump the UTI

Box 1. Clinical Features of Acute Uncomplicated Cystitis

syndromes that do not meet the aforementioned

description of simple cystitis as well as UTIs that occur

History

in patients with severe immunosuppression or with

Key method of diagnosis

significant anatomical abnormalities. Because compli-

Possible symptoms

• Dysuria

cated UTIs encompass a wide spectrum of syndromes,

• Urinary frequency

there is no singular approach to managing them.

• Urinary urgency

Therefore, rather than using the binary of uncompli-

• Suprapubic pain

cated versus complicated UTIs, this text discusses an

• “Feels like prior treated UTI”

approach to the individual syndromes that fall under the

• Absence of vaginal symptoms

umbrella of “complicated” UTI such as pyelonephritis,

• Absence of systemic symptoms (shaking chills, rigors)

prostatitis, or catheter-associated UTIs.

• Absence of upper tract symptoms

Diagnosis of UTIs is primarily made by the presence of

Other Diagnostics^a

typical symptoms and can be confirmed by 2 main labo-

Not required for all patients

ratory tests: urinalysis and urine cultures. Urinalysis can

• Urinalysis: pyuria (approximately >10 WBC/HPF), pres-

help with diagnosis of UTIs. There are 2 main urinalysis

ence of “many” bacteria

tests: urine microscopy and urine dipstick. Urine micro-

• Urine dipstick: + nitrite, + leukocyte esterase

• Urine culture with >105 CFU growth of a pathogenic

scopy can identify the presence of white blood cells

organism

(WBCs) in urine, which is termed pyuria. Having ≥10

WBCs/μL in urine is suggestive but not diagnostic of a

Abbreviations: CFU, colony-forming units; HPF, high-power field; UTI, urinary

tract infection; WBC, white blood cells.

UTI. The greatest value of checking for pyuria lies in its

^aThese tests can increase likelihood of a cystitis diagnosis but are not diagnostic

negative predictive value, which is reported to be more

on their own. Clinical context is necessary to interpret results.

than 85%. Therefore, without pyuria it is unlikely that a

patient has a UTI.

The advantage of a urine dipstick is that it is usually

case 1, can be sufficient to make a clinical diagnosis (Box 1)

more readily available than microscopy or culture. The

and recommend empiric treatment. An example would be

2 main tests in a urine dipstick that can aid with UTI

the combination of dysuria and urinary frequency without

diagnosis are leukocyte esterase and nitrite. Leukocyte

vaginal discharge or irritation, which has a reported positive

esterase, an enzyme released by lysed WBCs, acts as a

likelihood ratio of 24 for the diagnosis of a UTI. Patients,

surrogate marker for pyuria. Nitrites in the urine are

especially if they have had prior UTIs like this patient, often

attributed to the ability of some Gram-negative bac-

recognize the symptoms and identify when they have a UTI.

teria like E coli (the most common cause of UTIs) to

One study found that self-diagnosis has a positive likelihood

convert urine nitrate to nitrite. Positive nitrite on a

ratio of 4.

urine dipstick can therefore be an indicator for the

The following are examples of situations where a uri-

presence of bacteria in the urine (bacteriuria) and

nalysis and urine culture should be sent when evaluating a

specifically Gram-negative bacteria. One of the limi-

patient for a UTI:

tations of this test is that it would not detect bacteri-

• Signs or symptoms of upper tract disease or systemic

uria with organisms that do not have the biochemical

illness.

ability to create nitrite such as Enterococci and Pseudomonas

• Atypical symptoms, such as a patient who has dysuria

species. Additionally, a false-positive nitrite can be

and vaginal symptoms that are also suggestive of

seen in patients who use phenazopyridine, which is a

vaginitis.

common over-the-counter urinary analgesic in the

• Patients at high risk of developing complications, such as

United States. The reported sensitivity of both leuko-

those who are immunocompromised or have urological

cyte esterase and nitrite for detecting bacteriuria

abnormalities.

was variable, but the specificity was found to be more

• Patients at risk of infection with multidrug-resistant or-

than 90%.

ganisms (MDRO), such as those with a history of in-

Midstream voided urine cultures are a more direct

fections with MDROs or who have had recent courses of

way to assess the presence of pathogenic bacteria in the

antibiotics or a recent hospitalization.

urine. Bacteriuria in some cases represent contamina-

• Lack of improvement or progression of symptoms after

tion; however, in symptomatic patients this could

about 48-72 hours of initial empiric antibiotics.

help confirm the diagnosis of a UTI. The classic cutoff

for a positive urine culture to reflect the presence of

Another important test to consider is a pregnancy

bladder bacteriuria has been >10⁵ colony-forming

test in women of childbearing age. Pregnancy can affect

units (CFU)/mL.

the threshold to treat UTIs and the type of antibiotics

Testing with urinalysis or urine culture up front is not

used; therefore, it is important to obtain a pregnancy

indicated in most cases of uncomplicated cystitis. Having

test if it is challenging to ascertain the likelihood of

classic symptoms of acute uncomplicated cystitis, as in

pregnancy with history alone. See Table 1 for a brief

AJKD Vol 83 | Iss 1 | January 2024

Al Lawati et al

Table 1. Safety of Oral Antibiotics in Pregnancy

FDA Pregnancy

Antibiotic

Risk Category^a

Comment

Nitrofurantoin

Can be used during the first and second trimester. Avoid use

in the last trimester due to the risk of hemolytic anemia in the

newborn.

Trimethoprim-sulfamethoxazole

Avoid use if there are alternatives. Use in the first trimester is

(TMP-SMX)

associated with an increased risk of fetal neural tube

defects. In the third trimester there is an increased risk of

hyperbilirubinemia and kernicterus. If necessary for use, the

second trimester would be the safest window.

Fosfomycin

Can be used.

Oral β-lactams (eg, amoxicillin-

Recommended for use in pregnancy.

clavulanic acid or cefpodoxime)

Fluoroquinolones (eg,

Avoid use if there are alternatives.

ciprofloxacin)

The risk-benefit balance needs to be assessed with use of any medication in individual patients. Consider involving their obstetrician if there are any concerns.

FDA Pregnancy Risk Categories:

• Category A: No risk in human studies.

• Category B: No risk in animal studies.

• Category C: Risk cannot be ruled out. There are no satisfactory studies in pregnant women, but animal studies

demonstrated a risk to the fetus; potential benefits of the drug may outweigh the risks.

• Category D: Evidence of risk. Studies in pregnant women have demonstrated a risk to the fetus; potential benefits of the

drug may outweigh the risks.

• Category X: Contraindicated. Studies in pregnant women have demonstrated a risk to the fetus; and/or human or animal

studies have shown fetal abnormalities. Risks of the drug outweigh the potential benefits.

overview of the safety of common oral antimicrobials

Review of Question 1

in pregnancy.

This patient had symptoms that would be classic for simple

cystitis (burning, frequency, suprapubic pain), so she can be

started on treatment without confirmatory laboratory testing.

Empiric Treatment

Of the treatment options listed, nitrofurantoin is the only

One of the main first-line agents for the treatment of acute

first-line agent. Ciprofloxacin should be reserved for pyelo-

uncomplicated cystitis is oral nitrofurantoin for 5 days

nephritis or more complicated infections, and β-lactams such

(Table 2). Fosfomycin is an acceptable alternative if

as amoxicillin are second-line agents. Thus, the answer is (c),

nitrofurantoin cannot be used. It is important to note that

prescribe nitrofurantoin 100 mg twice daily for 5 days.

both nitrofurantoin and fosfomycin should be avoided if

early pyelonephritis is suspected because they have poor

Pyelonephritis

drug penetration to renal parenchyma. Trimethoprim-

sulfamethoxazole can also be used empirically as a first-

Case 1, continued: The patient then developed subjective

fevers and right lower back pain despite having taken the

line agent except in cases where local resistance rates to

nitrofurantoin prescribed empirically by urgent care for 3 days.

Enterobacteriales (like E coli) exceed 20% or in patients who

The diagnosis is pyelonephritis, and the urine cultures

have used trimethoprim-sulfamethoxazole for an infection

grew > 100,000 CFU/mL E coli which was resistant to nitro-

in the past 3 months.

furantoin and trimethoprim-sulfamethoxazole but susceptible to

Oral β-lactams such as amoxicillin-clavulanate or cefpo-

ciprofloxacin. She was switched to ciprofloxacin 500 mg twice

doxime are effective second-line agents in treating UTIs.

a day. She showed improvement in her symptoms by day 2 of

They are considered second-line agents because there are

treatment and resolution of all symptoms by day 3.

limited data suggesting their inferior efficacy and a longer

duration of administration is needed compared with other

Question 2: How many total days of ciprofloxacin

medications. They should only be used if the previously listed

would be recommended for this patient?

first-line options are not feasible due to allergy, availability,

(a) Treat for a total 3 days

or resistance. Fluoroquinolones like ciprofloxacin are often

(b) Treat for a total 7 days

effective in treating UTIs but are not recommended as first-

(d) Treat for a total 21 days

line agents for uncomplicated cystitis if there are other oral

(e) Determine treatment based on repeat urine culture re-

alternatives. This is due to their side-effect profile and to

sults at day 7

mitigate the increasing rates of quinolone resistance. They are

reserved for more serious infections such as pyelonephritis.

For the answer to this question, see the following text.

AJKD Vol 83 | Iss 1 | January 2024

Al Lawati et al

Table 2. Oral Antibiotics for the Management of Cystitis and Pyelonephritis

Antibiotic

Acute Uncomplicated Cystitis

Pyelonephritis

Nitrofurantoin

• First-line agent

• Avoid due to suboptimal concentrations in

• 100 mg twice daily for 5 daysa

renal parenchyma

Trimethoprim-

• First-line agent

• Can be used if bacteria are identified to be

sulfamethoxazole

• 1 DS tablet twice daily for 3 days^a

susceptible.

• Avoid if used in the past 3 months or if

• 1 DS tablet twice daily

prevalence of local resistance is known to

• Note: The Infectious Diseases Society of

exceed 20%. (Rates of TMP-SMX

America (IDSA) recommends 14 days, but

resistance in E coli isolates in most of the

more recent data indicate that 7 days

United States exceed 20%.)

would be adequate provided the patient is

improving clinically.

Fosfomycin

• First-line agent.

• Avoid due to suboptimal concentrations in

• 3 g as 1 dose

renal parenchyma

Oral β-lactams (eg,

• Use only if the above first-line agents

• Not recommended as an initial agent.

amoxicillin-clavulanic acid

cannot be used

• Can consider using oral β-lactam agent if

or cefpodoxime)

• Example (not comprehensive list):

pathogen known to be susceptible and

> Amoxicillin, clavulanic acid 500/125 mg

after the patient receives an initial intrave-

twice daily for 5-7 days^a

nous dose of a long-acting parenteral

> Cefpodoxime, 100 mg twice daily for 5-

antimicrobial, such as 1 g of ceftriaxone.

7 days^a

Fluoroquinolones (eg,

• Effective but use only if alternative oral

• Ciprofloxacin 500 mg twice daily for 7

ciprofloxacin)

antimicrobials for acute cystitis are not

days

available or possible

• Example: Ciprofloxacin 250 mg twice daily

for 3 days^a

Doses listed in this table are for creatinine clearance > 60. Abbreviations: DS, double strength; TMP-SMX, trimethoprim-sulfamethoxazole.

Duration of therapy for cystitis are based on guideline recommendations for women. For uncomplicated cystitis in men, consider duration of w7 days provided there is no

evidence of prostatitis.

Pyelonephritis is a UTI that extends to the kidneys. The

pyelonephritis because of their suboptimal penetration to

typical symptoms include flank pain, fevers, rigors, nausea,

renal parenchyma (Table 2). With regard to the duration

or vomiting. In contrast to cystitis, obtaining urinalysis and

of treatment, there have been multiple randomized clinical

urine cultures is recommended for all cases of suspected

trials showing that 7 days of antibiotic therapy was non-

pyelonephritis.

inferior to longer courses for treatment of pyelonephritis

The diagnosis of pyelonephritis should be made by

in most patients.

clinical assessment and laboratory testing (urinalysis and

urine culture). Imaging is not required for all comers and

Review of Question 2

can be reserved for cases where the patient is critically ill,

The patient’s fever and flank pain indicated that she

not improving on initial therapy, or suspected to have an

had progressed to pyelonephritis. The recommended

obstruction or a complication. Complications of pyelo-

duration for treatment of pyelonephritis with ciprofloxacin

nephritis include but are not limited to sepsis, acute renal

is 7 days, provided the patient is clinically improving as in

failure, renal or perinephric abscess, kidney stones (eg,

this case. Tests of the cure with repeat urine cultures is not

staghorn calculi), and emphysematous pyelonephritis (a

recommended. Thus, the answer is (b), 7 days.

serious necrotizing infection). Computed tomography

(CT) scan of the abdomen with intravenous (IV) contrast

Case 2: A 53-year-old man with diabetes mellitus, incom-

is typically the primary mode of imaging in the majority

plete bladder emptying, and a deceased donor renal trans-

of these cases. Renal ultrasound is less sensitive than a CT

plant 2 years ago who is taking mycophenolate mofetil and

scan but is a reasonable alternative for patients where

tacrolimus presents to the emergency department (ED) with

exposure to radiation or contrast is of concern. Manage-

5 days of dysuria, urinary frequency, and fatigue. On the fifth

day, he developed fever with rigors, so he presented to the

ment of these complications may require drainage of

ED. In the ED he is hemodynamically stable with WBC of

collections and a multidisciplinary approach involving

15,000 with urinalysis showing >182 WBC, 2 red blood

specialties such as urology, interventional radiology, or

cells (RBC), + leukocyte esterase, and 4+ bacteria. Within

infectious diseases.

24 hours, his urine and a single blood culture bottle grow E

In patients who are clinically stable and can tolerate oral

coli that is multidrug resistant (see the table below). His renal

medications, the treatment can be via a highly bioavailable

transplant ultrasound is normal. The patient has an estimated

drug such as oral ciprofloxacin. Note that some of

glomerular filtration rate (eGFR) of 48 (creatinine clearance

the agents typically used for cystitis (nitrofurantoin and

of 50) and normal electrolytes; he clinically responds within

fosfomycin) are not recommended for use with

24 hours of appropriate antibiotic therapy.

AJKD Vol 83 | Iss 1 | January 2024

Al Lawati et al

this drug class, where the concentration in the urine usually

E coli (Urine) > 10⁵ CFU

exceeds the intermediate MIC. The pharmacokinetics are not

MIC

Interpretation

comparable for the bloodstream where the concentration is

Ampicillin-Sulbactam

≥32

Resistant

unlikely to exceed the intermediate MIC, thus, this strategy

Ceftriaxone

≥4

Resistant

should be avoided in bacteremia. Finally, although the use of

Meropenem

<0.25

Susceptible

trimethoprim-sulfamethoxazole in this case is reasonable

Ertapenem

Susceptible

based on the favorable eGFR of 48 (creatinine clear-

Ciprofloxacin

0.5

Intermediate

ance > 30), many transplant recipients may not fit this

Nitrofurantoin

≥128

Resistant

description. In those cases, eGFR should factor into the

Trimethoprim-

Susceptible

sulfamethoxazole

antimicrobial selection and dosing, which are complex and

Fosfomycin

≥256

Resistant

not generalizable to a case-based review. Thus, in this case

Abbreviations: CFU, colony-forming unit; MIC, minimum inhibitory concentration.

with the caveats as described, the best answer listed to this

question is (c).

Question 3: With which antibiotic and for what dura-

Additional Readings

tion would you treat this patient?

➢ Bent S, Nallamothu BK, Simel DL, Fihn SD, Saint S.

(a) 3 days of ertapenem

Does this woman have an acute uncomplicated urinary

(b) 7 days of nitrofurantoin

tract infection? JAMA.

2002;287(20):2701-2710.

https://doi.org/10.1001/jama.287.20.2701

ertapenem

➢ Drekonja DM, Trautner B, Amundson C, Kuskowski M,

(d) 21 days of trimethoprim-sulfamethoxazole

Johnson JR. Effect of 7 vs 14 days of antibiotic therapy

(e) 14 days of ciprofloxacin

on resolution of symptoms among afebrile men with

For the answer to this question, see the following text.

urinary tract infection: a randomized clinical trial.

JAMA.

2021;326(4):324-331. https://doi.org/10.1

001/jama.2021.9899

Comparable to the second part of case 1, this is a case

➢ Eliakim-Raz N, Yahav D, Paul M, Leibovici L. Duration

of pyelonephritis but in a renal transplant recipient and

of antibiotic treatment for acute pyelonephritis and

has an associated bloodstream infection. In this case,

septic urinary tract infection-7 days or less versus

imaging of the genitourinary tract is performed to

longer treatment: systematic review and meta-analysis

exclude an abscess or other transplant complication

of randomized controlled trials. J Antimicrob Chemother.

because these will likely impact management if found.

2013;68(10):2183-2191.

https://doi.org/10.1093/

The choice and duration of antibiotic in this case involves

jac/dkt177x

consideration of the host, the pathogen’s susceptibility

➢ Expert Panel on Urological Imaging; Smith AD, Niko-

profile, and the associated bloodstream infection. The

laidis P, Khatri G, et al. ACR appropriateness criteria

Infectious Disease (ID) Committee of Practice for the

acute pyelonephritis: 2022 update. J Am Coll Radiol.

American Society of Transplantation recommends 14 days

2022;19(11S):S224-S239. https://doi.org/10.1016/j.

of treatment for complicated UTI/pyelonephritis. Yet in

jacr.2022.09.017

practice there is variability, as published by authors who

➢ Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ.

surveyed the ID committee’s providers and transplant

Urinary tract infections: epidemiology, mechanisms of

nephrologists.

infection and treatment options. Nat Rev Microbiol.

2015;13(5):269-284.

https://doi.org/10.1038/

Review of Question 3

nrmicro3432

In general, 14 days of treatment is favored, but shorter du-

➢ Goldman JD, Julian K. Urinary tract infections in

rations are sometimes utilized based on newer data. Further,

solid organ transplant recipients: guidelines from

when acceptably bioavailable oral options exist, the total

the American Society of Transplantation Infectious

duration of treatment does not need to be parenteral. For that

Diseases Community of Practice. Clin Transplant.

reason, answer (a) is incorrect; 3 days of ertapenem only is

2019;33(9):e13507.

https://doi.org/10.1111/

an insufficient course for pyelonephritis in general. Answer

ctr.13507

(b) is incorrect as well; nitrofurantoin should only be used

➢ Gupta K, Hooton TM, Naber KG, et al. International

for cystitis and never for upper tract disease or bacteremia.

clinical practice guidelines for the treatment of acute

Although treatment with trimethoprim-sulfamethoxazole

uncomplicated cystitis and pyelonephritis in women: a

alone is reasonable, a 21-day course is excessive without

2010 update by the Infectious Diseases Society of

abscess and raises the risk of complications, thus making

America and the European Society for Microbiology

answer (d) incorrect. Answer (e) is also incorrect, while

and

Infectious

Diseases.

Clin

Infect

Dis.

some providers might choose to use a quinolone with an

2011;52(5):e103-120. https://doi.org/10.1093/cid/

intermediate MIC for cystitis, given the pharmacokinetics of

ciq257 +ESSENTIAL READING

AJKD Vol 83 | Iss 1 | January 2024

Al Lawati et al

➢ Kumar R, Pereira M, Taimur S, True K, Detwiler R, van

difficile infection. One study by Rotjanapan and colleagues

Duin D. Duration of antibiotic treatment for acute graft

showed that the 3-month risk of C difficile was 8.5 times

pyelonephritis: what’s the standard of care? Transpl Infect

higher in patients who were treated for ASB. Therefore,

Dis.

2023;25(1):e13996. https://doi.org/10.1111/

screening or treatment for ASB should be avoided in most

tid.13996

patients.

➢ McAteer J, Lee JH, Cosgrove SE, et al. Defining the

The main exceptions to this are the following 2 pop-

optimal duration of therapy for hospitalized patients

ulations (Box 2). The first is pregnant women because

with complicated urinary tract infections and associated

treatment decreases the risk of pyelonephritis and negative

bacteremia. Clin Infect Dis.

2023;76(9):1604-1612.

fetal outcomes. The second population that may benefit

https://doi.org/10.1093/cid/ciad009

from a course of antibiotics are patients who will undergo

➢ Medina M, Castillo-Pino E. An introduction to the

urologic procedures associated with significant mucosal

epidemiology and burden of urinary tract infections.

bleeding and trauma (eg, transurethral surgery of the

Ther Adv Urol. 2019;11:1756287219832172. https://

prostate or the bladder, or percutaneous stone surgery).

doi.org/10.1177/1756287219832172

Relatedly, most of the data available do not support

➢ Voora S, Adey DB. Management of kidney transplant

treatment of ASB in renal transplant patients. This, how-

recipients by general nephrologists: core curriculum

ever, continues to be studied; currently, because of the lack

2019. Am J Kidney Dis. 2019;73(6):866-879. https://

of data on the immediate transplant period (1-2 months

doi.org/10.1053/j.ajkd.2019.01.031

after transplant), many centers will treat ASB if found

➢ Yahav D, Franceschini E, Koppel F, et al. Seven versus

coincidently during this time, but they do not routinely

14 days of antibiotic therapy for uncomplicated Gram-

screen for such.

negative bacteremia: a noninferiority randomized

controlled trial. Clin Infect Dis. 2019;69(7):1091-1098.

Review of Question 4

https://doi.org/10.1093/cid/ciy1054

Pregnancy is an indication for the treatment of ASB, so the

answer is (a). Uncomplicated diagnostic cystoscopy or

Foley catheter placement have a low risk of infection.

Asymptomatic Bacteriuria

Although urine culture results can help guide the standard

1-2 doses of perioperative prophylaxis for cystoscopy, a

Case 3: A 33-year-old woman with diabetes mellitus pre-

UTI treatment course with multiple days of antibiotics is

sents to her primary care doctor’s office for a routine follow-

considered unnecessary. Patients with solid organ trans-

up visit. She feels well and has no acute complaints. The

urine sample she submitted for annual screening for albu-

plants, other than early renal transplant, do not require

minuria was also sent for urine microscopy and urine culture

treatment for ASB.

due to a processing error. The urine microscopy was notable

for 5-10 WBC/high-power field (HPF), and the urine cul-

Additional Readings

tures grew more than

10⁵

CFU/mL of pan-susceptible

➢ Goldman JD, Julian K. Urinary tract infections in solid

Klebsiella oxytoca.

organ transplant recipients: guidelines from the

American Society of Transplantation Infectious Diseases

Question 4: In which of the following scenarios would

Community of Practice. Clin Transplant. 2019;33(9):e13507.

antibiotic treatment targeted at urine culture results

https://doi.org/10.1111/ctr.13507

be indicated for this patient?

➢ Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice

(a) Pregnancy

guideline for the management of asymptomatic

(b) Elective hernia repair scheduled in the next 48 hours

bacteriuria: 2019 update by the Infectious Diseases

(d) Placement of a Foley catheter

Society of America. Clin Infect Dis. 2019;68(10):e83-

(e) Liver transplant in the past year

e110. https://doi.org/10.1093/cid/ciy1121 +ESSENTIAL

READING

For the answer to this question, see the following text.

➢ Rotjanapan P, Dosa D, Thomas KS. Potentially inap-

propriate treatment of urinary tract infections in two

Asymptomatic bacteriuria (ASB) is defined as ≥10⁵

Rhode Island nursing homes. Arch Intern Med.

CFU/mL in a voided urine specimen without signs or

2011;171(5):438-443.

https://doi.org/10.1001/

symptoms attributable to UTI. This is regardless of

archinternmed.2011.13

whether pyuria is present. ASB is a common benign

finding in many populations including healthy women,

residents in long-term care facilities, and patients with

Box 2. Main Indications to Treat Asymptomatic Bacteriuria

urinary tract abnormalities. Studies have shown that anti-

• Pregnancy

microbial treatment for the majority of patient populations

• Urologic procedures associated with mucosal bleeding or

with ASB does not confer significant benefit but can in-

trauma

crease the risk of antimicrobial resistance or Clostridioides

AJKD Vol 83 | Iss 1 | January 2024

Al Lawati et al

Review of Question 5

Catheter-associated Urinary Tract Infection

The CDC surveillance definition of CAUTI includes the 3

Case 4: You are seeing a 64-year-old man with diabetes mel-

criteria detailed previously. Of the answer choices, only

litus and heart failure with reduced ejection fraction who was

(b) is consistent with 1 of the criteria: urine culture with

admitted to the cardiac intensive care unit with acute decom-

1 organism with a bacterium of >10⁵ CFU/mL. Note that

pensated heart failure. He did not have a fever or leukocytosis

indwelling catheters only need to be in place for

on presentation. An indwelling urinary catheter was placed on

consecutive days in an inpatient location to meet the

hospital day 1 to assist with intravenous diuresis. On hospital

surveillance definition. Also, although CAUTI often are

day 4, the patient was noted to have a fever to 38.5 C. Blood

caused by Gram-negative organisms, Enterococcus spp,

cultures were drawn and are pending. The urinalysis revealed

moderate leukocyte esterase and >182 WBC/HPF. The urine

Staphylococcus spp, and Candida spp are also possible causa-

culture grew >100,000 CFU/mL of Klebsiella pneumoniae.

tive pathogens.

Question 5: Which of the following is consistent with

Additional Readings

the Centers for Disease Control and Prevention (CDC)

surveillance definition of a catheter-associated urinary

➢ Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis,

tract infection (CAUTI)?

prevention, and treatment of catheter-associated uri-

(a) Indwelling catheter in place for at least 2 weeks

nary tract infection in adults: 2009 international clin-

(b) Urine culture with 1 organism with bacterium of >10⁵

ical practice guidelines from the Infectious Diseases

CFU/mL

Society of America. Clin Infect Dis. 2010;50(5):625-663.

https://doi.org/10.1086/650482 +ESSENTIAL READING

(d) Presence of E coli or other Gram-negative rod isolated in

➢ Raz R, Schiller D, Nicolle LE. Chronic indwelling

urine culture

catheter replacement before antimicrobial therapy for

(e) Admission to a hospital for less than 48 hours

symptomatic urinary tract infection. J Urol.

For the answer to this question, see the following text.

2000;164(4):1254-1258. https://doi.org/10.1016/

S0022-5347(0567150-9)

➢ National Healthcare Safety Network. Urinary tract in-

The CDC surveillance definition of a CAUTI necessitates

fections (catheter-associated urinary tract infection

that patients meet the following 3 criteria:

[CAUTI] and non-catheter-associated urinary tract

1. Indwelling catheter in place for more than 2 consecu-

infection [UTI]) events. US Centers for Disease Control

tive days in an inpatient location.

and Prevention, updated January 2023. https://www.

2. Urine culture with no more than 2 organisms present

cdc.gov/nhsn/pdfs/pscmanual/7psccauticurrent.pdf

and 1 organism with bacterium of >10⁵ CFU/mL.

➢ Weiner LM, Webb AK, Limbago B, et al. Antimicrobial-

3. Presence of at least 1 of the following: fever (38 C),

resistant pathogens associated with healthcare-

suprapubic tenderness, costovertebral angle pain or

associated infections: summary of data reported to

tenderness, urinary urgency, urinary frequency, or dysuria.

the National Healthcare Safety Network at the Centers

for Disease Control and Prevention, 2011-2014. Infect

The patient in case 4 above meets each of the 3 CAUTI

Control Hosp Epidemiol. 2016;37(11):1288-1301. https://

criteria. CAUTI is the most frequent health care-related

doi.org/10.1017/ice.2016.174

infection worldwide, and it has been associated with the

development of bacteremia and increased mortality. The

diagnosis of CAUTI can be difficult because pyuria is an

Acute Bacterial Prostatitis

expected finding in patients, and the symptoms are often

nonspecific if the catheter is still present.

Case 4, continued: After CAUTI was diagnosed in the

The treatment for CAUTI includes first discontinuing the

previous patient, he was started on intravenous ceftriaxone.

indwelling catheter or replacing the catheter (if still needed)

However, he continued to have temperatures above 38.0 C

if it has been in place for more than 2 weeks. Because urine

over the next 2 hospital days. A digital rectal examination

cultures from long-term indwelling catheters may reflect the

revealed that the patient’s prostate was tender and swollen.

A CT scan of his abdomen and pelvis showed a

microbiology of the catheter’s biofilm instead of the infection

heterogeneous-appearing prostate without abscesses or

in the bladder, obtaining a urine culture from a newly placed

other intra-abdominal pathology. The patient slowly begins to

catheter is recommended to guide antimicrobial therapy.

show clinical improvement, and you plan a treatment course

Antimicrobial therapy should be initiated in patients

for acute bacterial prostatitis (ABP).

with suspected CAUTI and tailored to the urine culture

results. Common bacterial causes of CAUTI include E coli,

Question 6: If ABP is diagnosed, as with the patient in

Klebsiella spp, Pseudomonas aeruginosa, and Enterococcus spp. A

case 4, how long should the patient receive antibiotics,

duration of 7 days of antimicrobial therapy is likely suf-

assuming continued clinical improvement?

ficient, provided that the patient improves clinically after

(a) 3-5 days

starting antimicrobials.

(b) 7 days

AJKD Vol 83 | Iss 1 | January 2024

Al Lawati et al

➢ Lipsky BA, Byren I, Hoey CT. Treatment of bacterial

prostatitis. Clin Infect Dis.

2010;50(12):1641-1652.

(d) 14-28 days

https://doi.org/10.1086/652861 +ESSENTIAL READING

(e) 42 days or longer

➢ Millan-Rodríguez F, Palou J, Bujons-Tur A, et al. Acute

For the answer to this question, see the following text.

bacterial prostatitis: two different sub-categories ac-

cording to a previous manipulation of the lower uri-

ABP is typically characterized by the abrupt onset of

nary tract. World J Urol. 2006;24(1):45-50. https://doi.

voiding symptoms and is also often accompanied by systemic

org/10.1007/s00345-005-0040-4

symptoms, though it can be difficult to diagnose because

helpful diagnostics are limited. As in this case, an indwelling

Case 4, continued: The patient clinically improves while on

parenteral ceftriaxone, and his discharge to home is planned.

urinary catheter or urinary manipulation is a risk factor for

He is transitioned to oral levofloxacin to complete a 21-day

development of ABP in men. On digital prostate palpation

antimicrobial course. On review of his discharge medications,

(which should be done gently to avoid risk of bacteremia),

you notice that the patient is currently taking the sodium/glucose

the prostate is often tender, swollen, and warm. In one

cotransporter 2 (SGLT2) inhibitor empagliflozin for his heart

retrospective, multicenter study of patients with an acute

failure.

prostatitis diagnosis, 63% had pain with palpation of the

prostate, and 83% had an “abnormal digital rectal exami-

Question 7: The above patient asks whether he should

nation.” Prostatic abscess is a rare complication of ABP in

continue the empagliflozin because as he has read it

general, but it may be more common in patients with ABP in

they can predispose individuals to infection. You

the setting of recent urinary tract manipulation. Imaging to

recommend:

(a) Continue the empagliflozin at same dose

assess for prostatic abscess should be pursued if clinical

(b) Continue the empagliflozin but decrease the dose

improvement is not seen with antimicrobial therapy. Imag-

ing modalities to diagnose prostatic abscess include prostate

(d) Stop empagliflozin and start an alternative medication for

ultrasonography, CT, and magnetic resonance imaging.

the patient’s diabetes

The management of ABP typically requires 2-4 weeks of

(e) Switch to a different SGLT2 inhibitor

antimicrobial therapy, ideally tailored to the results of the

For the answer to this question, see the following text.

urine culture if available. ABP is most commonly caused by

E coli, P aeruginosa, Klebsiella spp, and Enterococcus spp; in sexually

active men, Neisseria gonorrhoeae and Chlamydia trachomatis should

Though SGLT2 inhibitors (eg, empagliflozin, dapagli-

also be evaluated with urine nucleic acid amplification

flozin, canagliflozin) have been associated with genital

testing. Though most antibiotics will penetrate acutely

infections, the literature regarding their association with

inflamed prostate tissue as these patients improve clinically,

UTI is conflicting. In a large, recent population-based

care should be taken to ensure antimicrobial agents are

cohort study, SGLT2 inhibitor use was not associated

chosen that achieve adequate concentration in prostate tis-

with serious and nonserious UTI. If SGLT2 inhibitors are

sue such as fluoroquinolones or trimethoprim-

otherwise indicated for management of diabetes or heart

sulfamethoxazole.

failure, providers should generally not discontinue the

medications in the setting of UTI.

Review of Question 6

Review of Question 7

Though there is a relative paucity of data regarding optimal

Because SGLT2 inhibitors are not clearly associated with

treatment duration of ABP, most guidance recommends 2-

UTI, they can generally be continued if patients have UTI,

4 weeks of therapy. Therefore, the correct answer is (c),

especially if there are other clear risk factors for the

14-28 days.

development of UTI as was the case with this patient (the

presence of indwelling urinary catheter). The correct

Additional Readings

answer is (a) because no change is necessary.

➢ Brehm TJ, Trautner BW, Kulkarni PA. Acute and

chronic infectious prostatitis in older adults. Infect Dis

Additional Reading

Clin North Am. 2023;37(1):175-194. https://doi.org/1

➢ Dave CV, Schneeweiss S, Kim D, Fralick M, Tong A,

0.1016/j.idc.2022.09.004

Patorno E. Sodium-glucose cotransporter-2 inhibitors and

➢ Coker TJ, Dierfeldt DM. Acute bacterial prostatitis:

the risk for severe urinary tract infections: a population-

diagnosis and management. Am Fam Physician.

based cohort study. Ann Intern Med. 2019;171(4):248-

2016;93(2):114-120. +ESSENTIAL READING

256. https://doi.org/10.7326/M18-3136

➢ Etienne M, Chavanet P, Sibert L, et al. Acute bacterial

prostatitis: heterogeneity in diagnostic criteria and

Nephrostomy Tube

management. Retrospective multicentric analysis of 371

patients diagnosed with acute prostatitis. BMC Infect Dis.

Case 5: A 43-year-old woman with metastatic ovarian can-

2008;8:12. https://doi.org/10.1186/1471-2334-8-12

cer is admitted to the hospital for fever, nausea, vomiting, and

AJKD Vol 83 | Iss 1 | January 2024

Al Lawati et al

Ciprofloxacin is highly bioavailable, and the patient can

back and abdominal pain. She has bilateral nephrostomies

be switched to this to complete her course because she can

placed 3 months ago for tumor-related ureteral obstruction.

tolerate an oral medication. As a reminder, nitrofurantoin

They were last exchanged 3 weeks ago. Fresh urine

collected from the tube (not the urine collecting in the bag)

does not achieve adequate concentrations in the upper

grew a pan-susceptible E coli. Her blood cultures are without

urinary tract. Therefore, the correct answer is (d), switch

growth, and the CT scan shows that the left tube is malpo-

to oral ciprofloxacin for a total of 7-10 days of antibiotics.

sitioned and the left kidney had perinephric stranding with no

abscess. She was started on IV ceftriaxone. After 72 hours

Additional Readings

she had resolution of her fever and tolerated a full diet. Her

➢ Bahu R, Chaftari AM, Hachem RY, Ahrar K, Shomali W,

nephrostomy tube was exchanged, and the next one is

El Zakhem A, et al. Nephrostomy tube related pyelo-

scheduled in 4 weeks.

nephritis in patients with cancer: epidemiology,

infection rate and risk factors. J Urol. 2013;189(1):130-

Question 8: What is the most appropriate next step in

135. https://doi.org/10.1016/j.juro.2012.08.094

management?

➢ Kar M, Dubey A, Patel SS, Siddiqui T, Ghoshal U, Sahu

(a) Continue IV ceftriaxone for a total of 4 weeks (until next

exchange)

C. Characteristics of bacterial colonization and urinary

(b) Continue IV ceftriaxone for 10 days followed by oral

tract infection after indwelling of Double-J ureteral

ciprofloxacin until next exchange

stent and percutaneous nephrostomy tube. J Glob Infect

Dis. 2022;14(2):75-80. https://doi.org/10.4103/jgid.

next exchange)

jgid_276_21

(d) Switch to oral ciprofloxacin for a total of 7-10 days of

antibiotics

(e) Switch to oral nitrofurantoin for a total of 7-10 days of

Approaching Candiduria

antibiotics

Case 6: A 64-year-old man is admitted to the intensive care

For the answer to this question, see the following text.

unit after a coronary artery bypass graft procedure. A Foley

catheter was placed during the procedure. On postoperative

day 3, the patient has a fever of 38.3 C. Blood cultures are

Obstruction is a common indication for placement of

obtained and are pending. His urinalysis is notable for the

percutaneous nephrostomy tubes. It is important to note

presence of leukocyte esterase and >50 WBC/HPF. The

that the urine in a nephrostomy bag is not sterile and

urine culture ultimately grows >100,000 CFU/mL Candida

albicans.

therefore not appropriate for conducting microbiological

testing. If there is a clinical suspicion for UTI, testing

Question 9: What is the most appropriate next step in

should only be performed on fresh urine draining directly

management?

from the tube. If the patient is undergoing an invasive

(a) Initiate antifungal treatment with fluconazole.

procedure, urine can also be sampled directly from the

(b) Replace the indwelling urinary catheter and repeat the

renal pelvis. However, even when sampling directly from

urine culture.

the tube it is important to only test the urine if there are

clinical signs or symptoms of an infection because patients

(d) Replace the indwelling urinary catheter and start treat-

with nephrostomy tubes can have ASB. This does not

ment with fluconazole.

require treatment and was reported at a rate of w7.5% in a

(e) Initiate antifungal treatment with micafungin.

study involving patients with cancer.

For the answer to this question, see the following text.

Review of Question 8

There are limited data and no guideline recommendations

The task of clinicians when approaching patients with

on duration of therapy for pyelonephritis in patients with

candiduria is to determine whether the isolated Candida

percutaneous nephrostomies. However, extrapolating

indicates contamination, colonization, or infection. For

from the pyelonephritis and CAUTI approaches, 7-10 days

patients with indwelling catheters and Candida isolated from

of treatment would likely be adequate provided there is

urine culture, the catheter should be discontinued (if

clinical improvement and no abscess or other foreign

possible) and a repeat urine culture obtained to investigate

body. Treating patients routinely for a longer period of

whether Candida is still present. If an indwelling catheter is

time can lead to these patients being colonized with

still required, the catheter should be exchanged and a new

resistant organisms and can expose them to preventable

culture obtained to again assess for persistence of

drug toxicities. If a case is more complicated and does not

candiduria.

meet the conditions described, then we would recommend

If Candida is again isolated, the clinician must then

a multidisciplinary approach including involvement of an

determine whether the patient has continued colonization

infectious diseases team to decide on an appropriate

versus cystitis or upper tract infection. Note that pyuria is

duration of therapy.

an expected finding in patients who have indwelling

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Al Lawati et al

catheters and is not helpful in delineating colonization

Question 10: What advice would you give as an initial

versus infection. Treatment of Candida UTI is only indicated

intervention to this patient?

in cases of persistent candiduria in patients who have

(a) Prescribe continuous

antibiotic prophylaxis with

symptoms consistent with UTI without an alternative eti-

ciprofloxacin

ology (ie, concurrent bacteriuria). Imaging such as renal

(b) Start vaginal estrogen

ultrasound or CT abdomen/pelvis should also be obtained

in the setting of persistent candiduria to assess for

(d) Initiate episodic antibiotic prophylaxis with intercourse

obstruction and need for urology consultation.

(e) Explain to her that there are no evidence-based methods to

reduce the frequency of UTIs in postmenopausal women

For candiduria in patients without indwelling catheters,

the management approach is similar. First, a repeat clean-

For the answer to this question, see the following text.

catch urine sample should be obtained (or a specimen

from the catheter if clean catch is not feasible) to see if

Recurrent UTIs take many different forms. They can be

Candida is again isolated. If applicable, patients should also

precipitated by sexual intercourse most frequently in pre-

be assessed for the presence of concurrent vaginitis. For

menopausal women but also in postmenopausal women.

patients who reisolate Candida in urine, imaging is indicated

Postmenopausal women are especially prone to recurrent

to assess for obstruction; however, as with catheterized

UTIs due to the increased incidence of atrophic vaginitis

patients, treatment of candiduria is only indicated when

and changes in the vaginal microbiome precipitated by lack

patients have signs/symptoms consistent with UTI. Ex-

of estrogenization of the tissues in the vaginal and lower

ceptions to this management approach include patients

urinary tracts. A detailed review of this pathophysiology is

undergoing urologic procedures and neutropenic patients

included in the recommended reading.

for which asymptomatic candiduria should be treated.

In general, recurrent UTIs in men are often associated

with underlying structural issues leading to urinary

Review of Question 9

retention or the presence of an indwelling catheter.

The patient in case 6 has evidence of a possible UTI with

When undertaking the care of a patient with recurrent

fever and a urine culture from an indwelling urinary catheter

UTI, there is frequently no single intervention that “heals

growing C. albicans. Though this could be consistent with

all.” There are associations with recurrent UTIs related to

fungal CAUTI causing fever, the isolation of C. albicans may

sexual activity related to spermicidal contraceptives; if a

also represent colonization of the catheter. Empiric treatment

woman is using this form of contraception, changing to a

is not warranted at this stage. Replacement of the urinary

different agent may provide benefit. It is not clear that other

catheter (if the catheter cannot be removed all together)

behavior modifications such as early voiding after sexual

followed by repeating the urine culture should be pursued.

intercourse or increased hydration to precipitate more

Unless Candida is reisolated or there is clinical evidence of an

frequent urination are effective in isolation, but certainly

upper urinary tract obstruction, renal ultrasound is not

these are low-risk interventions that are easy to do.

necessary at this juncture. The answer is (b), replace the

For postmenopausal women, especially those in whom

indwelling urinary catheter and repeat the urine culture.

there may be associated incontinence, a pelvic examination

to exclude pelvic floor dysfunction or prolapse is advised. If

Additional Reading

there is no correctable anatomic issue, then vaginal estro-

gens are a well-tolerated, low-risk intervention to under-

➢ Kauffman CA. Diagnosis and management of fungal

take. Vaginal estrogens can be applied in many forms

urinary tract infection. Infect Dis Clin North Am.

including vaginal rings, creams, and tablets and may take

2014;28(1):61-74. https://doi.org/10.1016/j.idc.2

some careful feedback from the patient about her experi-

013.09.004 +ESSENTIAL READING

ences to find the most favorable preparation. Utilization of

supplements such as cranberry extracts and D-mannose have

Recurrent UTI

been tried, and some individuals may find benefit, but the

data are mixed (as presented in a recent Cochrane review).

Case 7: A 78-year-old woman comes to see her primary

Investigators are studying the use of vaginal probiotics,

care doctor after her third episode of cystitis in the last 9

which may have efficacy in combination with estrogens.

months. She notes that each episode was heralded by uri-

For those who are unable to derive benefit from these

nary frequency, urgency, and dysuria. She has no known

interventions, antibiotic prophylaxis is often tried. Post-

other medical conditions except for well-controlled hyper-

coital antibiotics can be effective in decreasing the inci-

tension on a single medication and osteoarthritis of her

dence of UTI and the most well-studied agent is

knees. Her pelvic examination does not reveal a prolapse but

trimethoprim/sulfamethoxazole. Continuous prophylaxis

does show changes consistent with atrophic vaginitis. Her

laboratory results reveal normal kidney function and no evi-

has been shown to be effective in clinical trials, but the

dence of diabetes. Her urinalysis on evaluation when she is

efficacy is lost once prophylaxis is stopped. Further, pro-

asymptomatic is normal, without any cells in sediment. She

phylaxis is not usually 100% effective, so UTIs will likely

asks for something to prevent further infections.

be less frequent but still present, and when they occur, the

AJKD Vol 83 | Iss 1 | January 2024

Al Lawati et al

organisms present are likely to have antimicrobial resis-

Conclusion

tance to the class of prophylactic drug.

Urinary tract infections are common and diverse, as

reviewed here. When approaching a patient with lower

Review of Question 10

urinary tract symptoms, not all patients require evaluation

The patient described in case 7 does not appear to have an

with urinalysis and urine culture. Not infrequently, how-

anatomic issue to which her recurrent UTIs can be ascribed.

ever, given the complexity of patients and the increasing

Further, she has changes on examination that are consistent

incidence of drug-resistant bacteria, urinalysis and urine

with atrophic vaginitis. Based on the sentinel randomized

culture can be an invaluable tool for management. Relat-

controlled trial of vaginal estrogens versus placebo per-

edly, isolation of bacteria or Candida from urine is not al-

formed by Raz and Stamm and published in 1993, this

ways pathogenic, necessitating careful consideration of the

patient will likely derive benefit from vaginal estrogens. This

reason for testing, the host, and any extenuating circum-

study not only demonstrated decreased antimicrobial use for

stances such as upcoming urologic procedures or preg-

UTI in the estrogen group over the follow-up period but

nancy. Like urine testing, imaging to exclude upper tract

also demonstrated other benefits such as decreased vaginal

involvement is not always necessary but in certain situa-

colonization with Enterobacterales with lower vaginal pH

tions, as outlined previously, is essential to guide treatment

and recolonization with Lactobacillus spp (normal vaginal

decisions. Finally, UTIs may be recurrent. In these situa-

flora). Thus, the correct answer is (b), start vaginal estrogen

tions, careful evaluation for potential modifiable risk fac-

as an initial intervention.

tors is beneficial. A number of pharmacologic

interventions have been studied, some less rigorously than

Additional Readings

others, and a standard approach to treating such recurrent

➢ Albert X, Huertas I, Pereiro I, Sanfelix J, Gosalbes V,

infections does not currently exist. As the world’s popu-

Perrotta C. Antibiotics for preventing recurrent urinary

lation ages and as medical advancements continue to in-

tract infection in non-pregnant women. Cochrane Database

crease, additional study into better approaches to prevent

Syst Rev.

2004;(3):CD001209. https://doi.org/10.1

UTIs is needed.

002/14651858.CD001209.pub2

➢ Cooper TE, Teng C, Howell M, Teixeira-Pinto A, Jaure A,

Article Information

Wong G. D-Mannose for preventing and treating urinary tract

infections. Cochrane Database Syst Rev. 2022;(8):CD013608.

Authors’ Full Names and Academic Degrees: Hawra Al Lawati,

https://doi.org/10.1002/14651858.CD013608.pub2

MD, Barbra M. Blair, MD, and Jeffrey Larnard, MD.

➢ Goldstein I, Dicks B, Kim NN, Hartzell R. Multidisci-

Authors’ Affiliations: Beth Israel Deaconess Medical Center,

plinary overview of vaginal atrophy and associated

Harvard University, Boston, Massachusetts.

genitourinary symptoms in postmenopausal women. Sex

Address for Correspondence: Barbra M. Blair, MD, Beth Israel

Med. 2013;1(2):44-53. https://doi.org/10.1002/sm2.17

Deaconess Medical Center, 110 Francis St, Lowry GB, Boston,

MA 02215-5501. Email: bblair@bidmc.harvard.edu

➢ Raz R, Stamm WE. A controlled trial of intravaginal

Support: None.

estriol in postmenopausal women with recurrent uri-

Financial Disclosure: The authors declare that they have no

nary tract infections. New Engl J Med. 1993;329(11):753-

relevant financial interests.

756. +ESSENTIAL READING

Peer Review: Received March 24, 2023 in response to an invitation

➢ Sihra N, Goodman A, Zakri R, Sahai A and Malde S.

from the journal. Evaluated by 2 external peer reviewers and a

Nonantibiotic prevention and management of recurrent

member of the Feature Advisory Board, with direct editorial input

urinary tract infections. Nature Rev Urol. 2018;15:750-

from the Feature Editor and a Deputy Editor. Accepted in revised

776. https://doi.org/10.1038/s41585-018-0106-x

form August 7, 2023.

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