Our study shows that relapse/recurrence of a symptomatic and/or febrile documented bacteriuria in hematology patients ongoing FN after chemotherapy is a rare event, regardless of antibiotic course duration, and is not associated with increased mortality.
Studying UTI during profound neutropenia is challenging. Due to the absence of leukocyturia in FN, there is no definite evidence of the urinary origin of sepsis. Klaasen and al. showed that a decrease of circulating neutrophils resulted in the absence of leucocyturia in the case of UTI (13). As a result, urinalysis is an unreliable marker of UTI in FN (9,14,15).
Neutrophils being central actors of the antibacterial response, urinary sepsis might occur without inducing any symptoms in FN patients. Steinrucken and al. considered the diagnosis of UTI only when UTSs were present (10). By contrast, our study supported the fact that an authentic urinary sepsis may occur even in the absence of UTS as 18 episodes of bacteriuria were bacteremic,;among these, only 4 (22.2%) were associated with UTS.
A study conducted by Grigg et al. included episodes of FN in hematological patients with urine culture available (9). Among 362 episodes, UTS were present in 39 out of the 345 episodes with negative or contaminated urine culture and in 9 out of the 17 episodes with positive urine culture. Having included patients with indwelling bladder catheter may have biased the presence of UTS. Stringent exclusion criteria eliminating indwelling bladder catheter were applied to our patients leading to the exclusion of 45.5% of the selected patients but reinforcing the clinical value of UTS.
In our population, 14.2% of the episodes presented UTS, which may correspond to true UTI according to the definition of UTI in the general population (16). Several studies in FN patients have shown that UTSs were a poor marker for bacteriuria insofar as they can be absent even in the case of significant bacteriuria (10,14,17). In light of our data and without further specific studies, hematology patients with FN urosepsis should still be considered, even in the absence of UTS.
Asymptomatic bacteriuria, also named urinary tract colonization (defined by the presence of ≥105 CFU/mL bacteria in a urinary culture without signs or symptoms evoking a UTI in the general population), is frequent in women (1-16%) but anecdotal in men due to morphological and pathophysiological differences (16). Since UTS might be absent during UTI in FN patients, it remains impossible to differentiate UTI from asymptomatic bacteriuria. In a recent study, all bacteriuria in FN patient without UTS were defined as UTI (14). However, it seems important to emphasize that not all bacteriuria in FN patient are UTIs.
IL-6 and other neutrophilic activation markers to differentiate UTI and asymptomatic bacteriuria have been evaluated in elderly patients, but have yet to be tested in FN (18,19). Positron Emission Tomography, Computed Tomography and MRI, have proven to be useful tools in UTI diagnosis (20,21). Although it might be difficult to propose additional imaging to hematological patients with FN, who are frequently exposed to ionizing rays, these techniques might be interesting in differentiating asymptomatic bacteriuria and UTI.
Regarding treatment duration, there was no relapse or recurrence of bacteriuria in men treated with short duration antibiotic therapy ≤14 days, whereas two episodes of relapse occurred in women who had likewise received short treatment. Regarding women's UTI in unspecific conditions, several studies and a meta-analysis have shown the safety of antibiotic duration reduction to ≤7 days for UTI treatment (22,23). Evidence for men is scarcer. One randomized controlled study demonstrated that a 2-week treatment was not inferior to a 4-week treatment for prostatitis (24). In FN, there is no evidence suggesting that a longer treatment duration could be safer. Though the size of our cohort might be a bit small to formally conclude, no association between short treatment duration and relapse, recurrence, or mortality was detected. Nevertheless, our study showed that bacteriuria during FN still encouraged clinicians to prescribe a longer antibiotic therapy, given that 24/71 (33.8%) episodes in women and 16/34 (47.0%) episodes in men received long treatment despite quick resolution of fever. Since positive urine culture will potentially increase the duration and at times the spectrum of the adapted antibiotic therapy, the necessity for systematic screening in the onset of FN is questionable .
Systematic urinary testing in the absence of symptoms at the onset of FN was withdrawn from both the 2011 IDSA and the 2016 ESMO guidelines. The only scientific evidence nevertheless supporting this practice is the Grigg et al. study, which did not show a morbidity-mortality increase in patients whose urine was not screened (9). IDSA guidelines on asymptomatic bacteriuria in 2019 did not address this issue because of “lack of scientific evidence”(16). The two aforementioned studies showed that systematic urine culture at the onset of FN rarely altered the choice of antibiotic therapy, but a low number of bacteriuria episodes were studied, 12 for Steinrucken and al. and 17 for Grigg and al. (9,10). Moreover, they did not specify whether spectrum or duration modification was studied (9,10). Of note, the threshold of bacteriuria in these studies was ≥105 UFC/mL corresponding to the usual threshold for asymptomatic bacteria. We nevertheless chose lower thresholds of bacteriuria, corresponding to the French guidelines for UTI, as we considered that every bacteriuria could potentially be an UTI in the FN setting (12).
ECIL-4 recommended that “empirical antibiotics can be discontinued after 72 h or more of intravenous administration in patients who have been hemodynamically stable since presentation and have been afebrile for 48 h or more, irrespective of their neutrophil count or expected duration of neutropenia” (25). In the case of true UTI, the length of antibiotic therapy should be adapted in order to provide sufficient treatment to avoid relapsing infection. This is especially true in men, for whom recommended antibiotic duration for a documented UTI far exceeds the treatment duration of a fever of unknown origin during FN.
Our study had some limitations due to its retrospective nature. However, the database was double-checked to reduce methodological bias. Concomitant blood stream infection could still be secondary to digestive translocation with urinary excretion of bacteria. In two of the four episodes in which relapse/recurrence occurred, bacteria had acquired a novel resistance phenotype suggesting the acquisition of resistance during first-line antibiotic treatment, even though it cannot be formally demonstrated in this setting. These drawbacks could be effectively ruled out using sequence typing to compare bacteria strains in further prospective studies. No imaging was performed to confirm the presence of an active UTI, whereas it could be implemented in further studies.
In conclusion, relapse, recurrence or death linked to urosepsis were rare events in FN affecting hematology patients. Shorter antibiotic courses did not seem to be associated with poorer outcome. To distinguish asymptomatic bacteriuria from infection remained challenging in women. In men, however, withdrawal of systematic urinalysis at onset of FN could lead to insufficient urosepsis diagnosis and treatment. Further randomized controlled studies are needed to confirm the safety of urinalysis withdrawal at the onset of post-chemotherapy FN to reassure clinicians and to remove a critical trigger for antibiotic consumption.