Impact of Early Chemotherapy Resumption on the Outcome after Staphylococcus aureus Bacteremia in Patients with Solid Tumors: A Retrospective Study in a Single Tertiary Cancer Center in Japan

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Introduction
Te incidence rate of Staphylococcus aureus bacteremia (SAB) is about 20 to 50 cases per 100,000 population per year [1].SAB is a common adverse event in patients with solid tumors that often require interruption of planned cancer treatments, including systemic chemotherapy [2].Generally, multiprofessional support is essential for SAB treatment.Conditions such as early consultation with infectious disease (ID) specialists [3][4][5][6][7] and confrmation of negative blood cultures [8][9][10][11] are associated with a favorable SAB prognosis.Te vulnerability of oncologic patients to SAB is driven by immunosuppression due to cancer or chemotherapy and the vascular access devices used, including central venous catheters or peripherally inserted central catheters [12].Te recommended duration of antibiotic treatment for SAB in immunosuppressed patients is more than four weeks [8].A dilemma arises between infection control and cancer treatment in the medical oncology setting.Te timing of chemotherapy resumption is one of the most frequently asked questions.However, there are no guidelines regarding when to resume chemotherapy for SAB patients with solid tumors [10,13,14].We aimed to explore whether early resumption of chemotherapy yielded an unfavorable outcome for SAB in oncologic patients.

Methods
2.1.Study Design.Tis retrospective study was conducted at Shizuoka Cancer Center, a tertiary care facility in Japan.Clinical data were obtained from the electronic medical charts of patients who met the inclusion and exclusion criteria and were hospitalized in any clinical division of Shizuoka Cancer Center from January 1, 2011, to December 31, 2020.Te inclusion criteria were as follows: (1) age >18 years, (2) bacteriologically proven SAB, (3) pathologically proven solid tumor, and (4) having received antineoplastic chemotherapy within 90 days before the onset of SAB.Exclusion criteria were as follows: (1) no follow-up data after SAB (e.g., transfer to another hospital), (2) polymicrobial bacteremia, (3) no documentation of negative blood culture after SAB, (4) hormonal therapy as antineoplastic chemotherapy, or (5) hematologic malignancy.A preprint has previously been published [15].

Data Collection.
Two investigators obtained clinical information from the electronic medical records and extracted the data.Te variables included age, sex, Eastern Cooperative Oncology Group performance status (PS), cancer histology and stage, type of chemotherapy, presence of vascular access devices, control of infection sources, ID consultation, methicillin-resistant Staphylococcus aureus (MRSA), Pitt bacteremia score, serum albumin, and mortality.In addition, we collected data, including the number of days from negative blood culture to chemotherapy resumption and the number of deaths within 30 days after chemotherapy resumption.Te Institutional Ethics Review Board approved the study protocol of Shizuoka Cancer Center (approval number: J2020-167-2021-1-2). Te requirement for informed consent was waived because of the retrospective nature of this study.

2.3.
Defnitions.SAB was defned as at least one blood culture positive for S. aureus with clinically apparent signs and symptoms of sepsis [16], with a documentation of sepsis.Catheter-related bloodstream infection (CRBSI) was defned as a primary bloodstream infection in patients with a central venous or peripheral catheter that was present for at least 48 hours before the onset of bacteremia and had no identifable source of infection outside the catheter [17].Te severity of bacteremia was based on the Pitt bacteremia score [18].Te duration of antibiotic therapy was defned as the number of days patients received susceptible antibiotics based on bacteriological tests for the patient's isolate [19].Treatment failure included either (1) recurrence, defned as a return of SAB after completing an antibiotic course with negative blood cultures; (2) relapse, defned as a positive blood culture for S. aureus ≥ 48 hours after a negative blood culture during an antibiotic course; (3) 90-day all-cause mortality after initiation of susceptible antibiotics; and (4) 30-day all-cause mortality after the resumption of chemotherapy [20,21].We defned the early and late resumption groups by the median time from the negative blood culture date to the resumption of chemotherapy.
Figure 2 shows the duration distribution from the date of negative blood culture to the date of chemotherapy resumption among patients in the resumption group (n � 36).Te median duration was 17.5 days (range, 0-69 days).Two patients resumed chemotherapy ≥ 2 months after obtaining a negative blood culture: one patient developed SAB-related thrombophlebitis and osteomyelitis requiring 41 days of intravenous antibiotics, and the other had persistent bacteremia requiring 53 days of intravenous antibiotics.We further classifed the 36 patients into two groups based on the median days to resuming chemotherapy (approximately 17 to 18 days), which were defned as the early (n � 18) and late (n � 18) resumption groups.Te median days to chemotherapy resumption in each group were 13 (range, 0-16 days) and 25.5 days (range, 19-69 days), respectively.Baseline characteristics of the two groups are shown in Table 2, and no signifcant diferences were found except for age (58.0 vs. 67.0;p � 0.048).Filgrastim/peg-flgrastim was used for neutropenia in 2 of 2 patients in the early resumption group and 2 of 3 patients in the late resumption group.All these patients were not associated with treatment failures.All 38 patients performed an echocardiogram, and only one patient was diagnosed with infectious endocarditis.However, it was not associated with treatment failure.In terms of chemotherapy, only two patients in the early resumption group changed cytotoxic agents to targeted agents after the onset of SAB.Tey fully recovered without the event of treatment failures.Regarding SAB treatment failures (Table 3), one patient (2.8%) experienced SAB recurrence, and three out of the 36 who resumed chemotherapy (8.3%) died within 90 days after initiating antibiotics toward susceptible microorganisms.Tere was no SAB relapse or death within 30 days after the resumption of chemotherapy.One patient in the early resumption group developed SAB and underwent reinsertion of the central venous port after resolution of the previous SAB episode with antibiotics toward susceptible microorganisms and had SAB again because of central venous port infection 89 days after completing a course of antistaphylococcal antibiotics for the frst episode.Te 90-day all-cause mortality rates in the early and late resumption groups were 2/18 (11.1%) and 1/18 (5.6%), respectively.Two patients in the early resumption group died 22 and 43 days after the completion of antibiotics toward susceptible microorganisms, respectively.One patient in the late resumption group died 21 days after the frst SAB episode.Tese deaths were attributed to the underlying cancer progression without an apparent

Discussion
Tis is the frst study to assess the impact of chemotherapy resumption on the outcome of SAB in patients with solid tumors.First, we showed that early resumption of chemotherapy was not associated with unfavorable outcomes in patients with appropriate antistaphylococcal antibiotic treatment and confrmed negative blood cultures.Second, we characterized oncological SAB in contrast to nononcological SAB in terms of baseline characteristics, etiology, and treatment outcomes.Tese fndings may help understand oncological SAB and promote future studies.
Early resumption of chemotherapy is desirable for the treatment of many primary diseases.Our study showed that most oncologists opted to resume chemotherapy based on the necessity of controlling cancer in patients with metastatic disease receiving palliative chemotherapy.Te treatment failure rate was low in both the early-and late-resumption groups, which may be attributed to appropriate infection management.Previous studies have identifed favorable prognostic factors for SAB management, including undetected infective carditis [22,23], appropriate antibiotic choices, duration of antibiotic treatment [11],   Data are given as the number (%) of patients.* Relapse was defned as a positive blood culture for S. aureus ≥48 hours after a negative blood culture during antibiotic treatment.† Recurrence was defned as a positive blood culture for S. aureus after the completion of antibiotic treatment.
documentation of negative blood cultures, and ID consultation.In our study, all patients who resumed chemotherapy were referred to the ID physicians who managed antibiotics, screened for complications, and monitored blood cultures.
In cases of treatment failures, one case of recurrence in the early resumption group occurred 89 days after completing the initial SAB treatment.However, a new infection due to the insertion of the CV port after the completion of the previous SAB episode was considered.Te 90-day mortality rate was 8% (three patients) in this study, and all deaths occurred after completing the initial SAB treatment.Te deaths were not associated with antineoplastic chemotherapy or SAB episodes and were deemed related to the progression of primary diseases.Although the incidence of treatment failure in our study was rare, the early resumption of chemotherapy may not be directly associated with unfavorable outcomes in well-managed patients with SAB.Furthermore, most chemotherapies were frst-line treatments in the early resumption group; therefore, early resumption of chemotherapy during frst-line treatment may provide a potentially valuable oncologic beneft to patients with solid tumors.To clarify the characteristics of solid tumor patients with SAB, we compared the diferences between the resumption and nonresumption groups, as well as the diferences between our oncological SAB and previously reported SAB in the general population.Te proportion of patients with good PS (0-1) in the resumption group was 83% compared to 29% in the nonresumption group, which may primarily afect the physician's decision to resume chemotherapy.In addition, the use of molecular-targeted treatment was less common in the resumption group, which may be another feature of oncological SAB.Regarding the source of infection, CRBSI was the most common (65%), and skin and soft tissue infections were the least common (8%).However, SAB in the general population is characterized by a signifcant diference in major origins with CRBSIs (18.8-37.6%)and skin and soft tissue infections (14.8-25.7%)[9,19,24,25].In our study, the 90-day mortality rate was 8% (three patients), which was lower than that in the existing report of approximately 30% in the general population and 36% in patients with malignancy [9,[24][25][26][27].Tis discrepancy may be partially attributed to the general condition of patients at the time of SAB onset.Rieg et al. showed that the 90-day mortality rate was 31.5%, but severe sepsis and septic shock accounted for approximately 45% of patients, infuencing the high mortality rate [25].Another reason for the low mortality in our study may be the high proportion of CRBSI as a source of infection because many patients had central venous lines for chemotherapy in this study, and source control was relatively easy owing to catheter removal.Although all treatment failures in this study occurred in cases of CRBSI, we could not say any association between CRBSI and treatment failures, since two-thirds of the cases were CRBSI cases and the number of cases itself is small.Tese fndings suggest that early resumption of chemotherapy may be feasible without increasing the chance of treatment failure in patients with good PS at the onset of SAB and a wellcontrolled source of infection.
Tis study had several limitations.First, it was a retrospective cohort study, and patients did not follow the same treatment protocol, even after ID consultations.Second, this study was possibly underpowered because the number of treatment failures was small owing to the small sample size.Terefore, we could not conclude that there was a statistically signifcant relationship between treatment failures and early resumption of chemotherapy.Tird, patients with hematological malignancies were excluded; thus, the results cannot be generalized to all malignancies.Fourth, we combined the data on multiple solid tumors and antineoplastic chemotherapy agents, which should be considered a possible confounding factor in the analysis.Fifth, this study was conducted in a tertiary care facility specializing in cancer care, with a high rate of ID consultations.Tus, it is not easy to generalize our results to all facilities.However, if patients with SAB are appropriately managed, our results can be generalized to facilities without ID physicians.
In conclusion, treatment failures are generally rare regardless of the timing of chemotherapy resumption in SAB cases in patients with solid tumors with appropriate management of infection if the PS is low and the source of infection is well controlled.However, our study may imply the possibility that early resumption is not necessarily associated with unfavorable outcomes.Early resumption is benefcial for patients for whom chemotherapy, including palliative purposes, is an inevitable part of their treatment.Further research is required to validate these hypotheses leading to a better outcome with multiprofessional cancer care.

Figure 2 :
Figure 2: Histogram of time to resumption of chemotherapy after negative blood culture.Day 0 was defned as the day when a negative blood culture was taken.

Table 1 :
Figure 1: Study fowchart.Te cut-of time between early and late resumption groups was used as the median time for chemotherapy resumption (17.5 days).SAB, Staphylococcus aureus bacteremia.Characteristics of the patients with SAB during chemotherapy.

Table 2 :
Characteristics of the patients among early and late resumption of chemotherapy.

Table 3 :
Treatment failures of S. aureus bacteremia after chemotherapy resumption.