INTRODUCTION
When interviewing acutely ill psychiatric patients such as individuals with an acute psychotic break or during acute mania, it is often difficult to obtain reliable responses from patients, either due to paranoia, disorganization, minimization of symptoms, or just because of the overwhelming nature of their psychiatric afflictions. Acutely ill psychiatric patients should be understood as those patients meeting criteria for admission to an acute inpatient psychiatric unit[1]. It is therefore not surprising that under such circumstances, patients may be dismissive or unwilling to acknowledge symptoms of a urinary tract infection (UTI). When prescribers face this scenario, is it still clinically accurate not to prescribe antibiotics?
ASYMPTOMATIC BACTERIURIA DURING ACUTE PSYCHIATRIC ILLNESS
UTIs are diagnosed by a combination of positive findings on urinalysis and/or urine culture, as well as the presence of focal symptoms. The absence of the latter is deemed asymptomatic bacteriuria (ASB), in which, according to current guidelines, very few circumstances require treatment or even screening for UTIs. This short list includes pregnant women, patients undergoing specific urological procedures, and patients who are in the first three months following renal transplantation according to the Infectious Disease Society of America[2]. While there have been other special populations for which treatment or screening of ASB has been considered, there has been no mention of acutely psychotic or manic patients or individuals with severe major depressive disorder. From our perspective, this is problematic for the following reasons. Given the clinical context of interviewing this patient population, often, such patients will not meet criteria to receive antibiotics due to their unwillingness or inability to communicate focal genitourinary symptoms. There is limited evidence to guide clinicians on this difficult decision, yet there appears to be a bidirectional relationship between schizophrenia and infections. In one study of 136 patients, the prevalence of presumed UTIs was substantially higher among patients with acute psychosis than among controls: 35% of 57 acutely relapsed subjects, vs 5% of stable outpatients and 3% of controls, had a UTI. Moreover, this association may be specific to acute psychosis, as there was no difference in the prevalence of UTI between stable outpatients with schizophrenia and controls[3]. Another retrospective chart review of adults found that 20% of the 235 patients hospitalized for psychosis had evidence of UTI compared to 3% in healthy controls[4]. A separate prevalence study of 127 children and adolescents hospitalized for non-affective psychosis (n = 80) and major depressive disorder with psychotic features (n = 47) found the prevalence of UTI was 20% in non-affective psychosis and 9% in major depressive disorder with psychotic features. It also showed a greater proportion of manic symptoms among patients who had a UTI compared to those who did not[5]. Overall, there is some evidence showing increased prevalence of UTIs among acutely ill psychiatric patients, along with some evidence suggesting UTIs may be contributing to the acute relapse or severity of symptoms in these individuals. Beyond this, people with a psychiatric history, including those with psychotic illnesses, are perhaps more vulnerable to UTIs, creating a cyclical relationship that exacerbates both psychiatric illness and UTI. Several explanations have been proposed to explain the increased risk of infections in schizophrenia patients, including limited access to care, poor hygiene, chronic health problems, poor education, and genetic-environmental factors causing immune system dysfunction. There is also an association between antipsychotic use and UTIs[6]. The reasonings behind this association are unknown, but proposed mechanisms include their anticholinergic effects causing urinary retention and D2-receptor antagonism causing voiding dysfunction, both of which can increase susceptibility to UTIs[7,8].
Limitation of current evidence
An important point we have to acknowledge is that the current evidence, pointing to increased prevalence of UTIs in acutely psychiatric ill patients, relies on a few retrospective studies looking at associations and prevalence studies. A limitation of these data is the inability to definitively draw causal relationships between UTIs and acute psychiatric illness or relapse. Graham et al[4] cited several confounders that could not be controlled for, including poor hygiene, recent sexual activity, poor access to care, or treatment nonadherence. Additional confounders include medication use, psychosocial stress, and comorbid medical conditions, which may provide alternative explanations for this association. The evidence supporting the relationship between schizophrenia and infections in general is more robust. A retrospective study found an association between hospitalization for infection prior to diagnosis of schizophrenia and subsequently developing schizophrenia[9]. One proposed mechanism by Benros et al[10] after finding that autoimmune diseases and severe infections have an additive risk for developing schizophrenia suggests increased inflammation in both autoimmune diseases and infections increase permeability of the blood-brain barrier allowing the brain to be affected by immune components.
Another special population for consideration of treating ASB that has been well-studied is older patients with functional or cognitive impairment (i.e., dementia), due to concerns about their ability to accurately communicate classic genitourinary symptoms[11]. While it has been hypothesized that acute mental status changes in these patients could be attributed to ASB, it has largely been proven that screening for or treating ASB confers no benefit in this population[12-14]. For our purposes, this special population serves as a meaningful comparison to our population of interest; acutely ill psychiatric patients, as the similarities between the populations suggest that acutely ill psychiatry patients should also warrant consideration as a special population for treatment of ASB. Similarities include difficulty communicating focal genitourinary symptoms, higher prevalence of UTIs, and baseline cognitive deficits, including emerging evidence suggesting shared pathophysiology between psychiatric and neurodegenerative diseases[15]. Furthermore, the clinical differences between the populations suggest that although screening for or treating ASB confers no benefit for older patients with functional or cognitive impairment, the same conclusion will not necessarily translate to our population of interest, warranting further investigation. Key clinical differences between these two groups include difficulty assessing mental status changes in older patients with advanced dementia compared to more definite diagnosis of psychosis; differences in age; differences in risk factors for UTI, including those aforementioned; and differences in medical comorbidities. More research in this area is clearly needed. A potential first step could be a nationwide retrospective cohort study, to test whether treating ASB improves psychiatric outcomes in acutely ill individuals. Such a study could also help gauge the safety of treating ASB in acutely ill psychiatric patients.
Risks of treating ASB
Treatment of UTIs or ASB is not without risks. There is a systematic review that describes 15 cases of suspected antibiotic-associated psychosis during treatment of UTIs. It highlights an important risk to consider when starting antibiotics for UTIs, which may themselves be associated with psychosis. This raises a confounder whether the UTI has caused psychosis, the antibiotics used to treat it, or other confounders mentioned above. The study was unable to definitively establish causality for most cases, especially given all 5 male cases had previous psychiatric histories[16]. Furthermore, the prevalence of UTI antibiotic-associated psychosis is unknown but presumed to be low due to findings limited to case reports. Based on a study assessing the United States Food and Drug Administration Adverse Event Reporting System, trimethoprim-sulfamethoxazole had a 0.7% adverse event rate for psychotic symptoms, penicillins 0.8%, fluoroquinolones 2%, and nitrofurantoin 0.9%[17]. Comparatively, in 3 studies spanning children, adolescents, and adults hospitalized for psychosis, the mean prevalence of UTI was 20.5% (n = 86/419)[3-5]. We believe that the current prevalence studies show a markedly greater association between UTI and psychosis compared to the association between antibiotics used to treat UTIs and psychosis, especially if the patient had a past psychiatric history. Other than potentially inducing psychosis, there are reports of antibiotics eliciting seizures[18], a rare but serious side effect. Antimicrobials can also increase the risk of Clostridioides difficile infection (CDI), however, the data are mixed. One retrospective cohort study showed cumulative number of antibiotic exposures associated with increasing risk of CDI[19]. A more recent retrospective study published in 2019 found no difference in mortality or CDI within 30 days in patients with ASB treated with antibiotics compared with those who received no treatment[20]. Antibiotic stewardship programs have consistently identified treatment of ASB as a contributor to inappropriate antimicrobial use, which promotes resistance. Coupled with growing trends of antimicrobial resistance in bacteria implicated in UTIs[21] and the fact that positive urine cultures encourage antimicrobial use irrespective of symptoms[22], there is significant risk to both screening for and treating ASB that cannot be ignored in our proposed special population of acutely ill psychiatric patients.
CONCLUSION
Compared to older adults (specifically with cognitive or functional impairment), patients with schizophrenia or mood disorders have failed to be considered as a special population with unique diagnostic and therapeutic challenges in the context of ASB. While more research is needed, we believe that under the circumstances we describe of acutely ill psychiatric patients showing signs of a UTI in a urine analysis or urine culture, treatment should be provided after a multidisciplinary discussion about management that is unique to the patient’s presentation and individual risk factors. Although it is important to weigh the risk of antibiotic-associated psychosis, antibiotic side effects, and increased risk of antimicrobial resistance, we must acknowledge the risk of acute psychosis or mania, which is associated with increased morbidity and mortality[23,24]. Beyond this, more clinically relevant outcomes-driven research is needed to assess whether this historically marginalized patient population may benefit from screening for or treating ASB in the long term.
