Abstract
Background
Although Clostridium difficile infection (CDI) often results in severe manifestations due to toxin‐producing clostridium, the correlation between CDI and having a fever in gynecological malignancies is not completely understood.
Aims
The incidence, and clinical features, and clinical management of CDI in patients with gynecological malignancies who have fevers were investigated, and the clinical managements of this complication are discussed.
Methods and results
We retrospectively reviewed 485 patients newly diagnosed with invasive gynecological cancers who underwent anticancer treatment between July 2012 and December 2016. The diagnosis of CDI was performed using enzyme immunoassays for C difficile glutamate dehydrogenase and toxin A/B enzyme immunoassay. The cumulative risk of CDI was 9.5% (six of 63) in overall fever patients and 6.3% (six of 95) in patients with fever episodes. Two CDI patients (33.3%) did not show diarrheal symptoms, with the fever of unknown origin criteria prompting their CDI testing and diagnosis. CDI patients were treated using vancomycin or metronidazole without suffering from fatal clinical course. Overall, eight patients with gynecological malignancies were diagnosed with CDI, including two patients with fever lower than 38.5°C. The cumulative risk of CDI was 0.48% (eight of 1652) for all admitted patients and 1.6% (eight of 485) in those with gynecological malignancies. Of all the patients with confirmed CDI, only one had a history of administration of antibiotics prior to onset of CDI symptoms.
Conclusion
CDI does not always present with typical manifestations in malignancy patients. Investigation of CDI, regardless of gastrointestinal symptoms or history of antibiotic use, is warranted in cases of fever of unknown origin in gynecological malignancy.
Keywords: chemoradiotherapy, chemotherapy, Clostridium difficile infection, diarrhea, fever, gynecology
1. INTRODUCTION
Recent improvements in multiple lines of chemotherapy, surgical procedures, and supportive care have increased survival rates in gynecological malignancies. Infection risk is among the most common complications associated with anticancer therapy and often life‐threatening, not only in hematological cancer patients but also in solid organ tumors1.
Clostridium difficile–associated diarrhea (CDAD) is induced by C difficile infection (CDI), and pseudomembranous colitis is one of the clinical manifestations.2 CDAD was identified in the late 1970s as an antibiotic‐associated pseudomembranous colitis that develops due to toxins produced by the bacteria. It became more widely known due to outbreaks reported in the 1980s.3, 4, 5 Carmill et al4 described cases of outbreak of severe CDAD, wherein 175 patients were infected with CDAD within a 6‐month period, which led to death in 17 patients.
On the other hand, additional CDI‐related pathological features induced by anticancer therapy or antiviral drugs have been identified.6, 7 In fact, there are numerous clinical manifestations of CDI, and it is not always associated with diarrheal complications.8, 9, 10, 11, 12 As the disease advances, systemic complications including abdominal pain and distension, cellulitis, sepsis, abscess, arthritis, dehydration, hypoproteinemia, and electrolyte abnormalities are also evident. In severe cases (3%), hemorrhagic diarrhea occurs with extensive ulceration.
Both fever and leukocytosis are important disease markers predictive of serious infection. Wanahita et al10 reported that CDI was present in 25% of tertiary patients with white blood cell counts greater than 30 000 cells/mm3 and suggested that CDI should be considered for patients with leukocytosis in a tertiary hospital, even in the absence of diarrheal symptoms.12 Another report11 also presents similar findings in which a majority of the patients in hospital with unexplained leukocytosis had CDI. However, leukocytosis does not usually enhance the severity of infection due to some level of myelosuppression by the anticancer therapy.
Several clinical reports describe severe chemotherapy‐related CDAD in gynecological malignancies, especially in ovarian cancer.13, 14, 15, 16, 17 However, a detailed information regarding the correlation between fever and CDI in gynecological malignancies has not been extensively studied. Although our hospital's infection surveillance guidelines recommend the CDI test when CDAD is suspected, we encountered a patient with CDI complicated with high fever whose symptoms were not applicable to the warning indications for CDI. In the present study, we investigated the incidence of CDI in fever patients and clinical outcomes of gynecological malignancies. Furthermore, the clinical management and treatment of this complication are discussed.
2. MATERIALS AND METHODS
2.1. Patient population
We reviewed the clinical database for entries between July 2012 and December 2016 to identify patients with gynecological malignancies. The research protocol was approved by the Institutional Review Board at the Kagoshima Medical Center. These patients underwent both gynecology and urology treatment in the same hospital ward. During this research period, a total of 485 patients newly diagnosed with invasive gynecological malignancies at the Kagoshima Medical Center who underwent anticancer treatments such as surgery, chemotherapy, or radiotherapy were identified. The total number of admissions in this period was 1652 for anticancer treatment, including the treatment of complications or palliative care. After finishing treatment, the patients with gynecological malignancies received regular screenings for recurrence of gynecologic malignancies every 3 to 6 months. At each screening, general health status assessment, serum tumor markers measurement, routine cervical cytology, and pelvic examinations were conducted. Subject classification according to different cancer types—invasive cervical cancer, endometrial cancer, ovarian cancer, and others—was 201, 161, 109, and 14 patients, respectively.
In this study, fever was defined as 38.5°C or higher, and clinical data were extracted by reviewing electronic inpatient charts. Outpatients experiencing complications, except for nonserious cases such as influenza, were admitted and treated in the hospital. Some patients experienced multiple episodes of fever; therefore, a next fever episode was defined as occurring over 3 days after the healing of the previous episode. Patients were tested for CDI when the following complications were presented: (a) gastrointestinal symptoms such as diarrhea or abdominal pain; (b) fever of unknown origin; and (c) infection that did not respond to antibiotics. Enzyme immunoassay (EIA) for C difficile glutamate dehydrogenase and toxin A/B EIA in stool cultures were performed on those patients with suspected CDI. The patients with confirmed CDI were excluded based on these test results regardless of fever. Demographic data such as age, International Federation of Gynecology and Obstetrics (FIGO) stage, and histology were considered. Complications were assessed following the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
3. RESULTS
In the four‐and‐a‐half‐year period, 13.0% (63 of 485) of patients experienced fever (38.5°C of higher) at least once in our cohort, and 19 patients developed fever several times (twice, 12; three times, 5; four times, 1; eight times, 1). The total number of fever episodes was 95 in our study cohort. Table 1 shows the characteristics of these 63 enrolled subjects who experienced fever. The median age was 61.0 years, cervical cancer was the most common (41%) gynecological disease, and advanced cancer stage was seen in 65% (41 of 63) of the patients. Diarrheal complication was seen in 22% (21 of 95) of fever episodes, and antibiotics were intravenously administered in 75% (71 of 95) of fever episodes. Eighty‐two percent of patients had undergone anticancer treatment while developing a fever, while 19% of patients experienced fever in the absence of ongoing anticancer treatment.
Table 1.
Characteristics of all fever patients (n=63)
| Median age (range) | 64 (34‐95 years) |
|---|---|
| Disease | Number of Patients |
| Cervical cancer | 26 (41%) |
| Endometrial cancer | 21 (33%) |
| Ovarian cancer | 15 (24%) |
| Others | 1 (2%) |
| aFIGO stage | Number of Patients |
| I‐II | 22 (35%) |
| III‐ IV | 41 (65%) |
| Event number per patients | Number of Patients |
| 1 | 44 (71%) |
| 2 | 12 (19%) |
| 3 | 5 (8%) |
| 4 | 1 |
| 8 | 1 |
| Median White blood cell counts in all episodes (range) | 7090 (560‐36640) |
| Median C‐reactive protein in all episodes (range) | 8.4 (0.12‐34.5) |
| Complicated with diarrhea in all episodes | Number of Patients |
| bN/A | 74 (78%) |
| Present | 21 (22%) |
| Administering anti‐biotics at the fever up to over 38.5 degree in all patients | Number of Patients |
| bN/A | 24 (25%) |
| Present | 71 (75%) |
| Last anti‐cancer treatment | Number of Patients |
| bN/A | 17 (18%) |
| Surgery | 19 (20%) |
| Chemotherapy | 31 (33%) |
| Radiotherapy or Concurrrent chemoradiotherapy | 28 (29%) |
FIGO, International Federation of Gynecology and Obstetrics
N/A, not applicable
Six patients with fever were diagnosed with CDI concurrent with gynecological malignancies. None of the six patients suffered from recurrent CDI. All patients diagnosed with CDI were treated as inpatients in the hospital. The overall risk of CDI complicated with fever was 9.5% (six of 63) of fever patients and 6.3% (six of 95) of overall fever episodes, in our study cohort. The six cases of CDI were isolated occurrences and not a result of disease outbreak in our cohort. Detailed clinical courses of these six patients are shown in Table 2. Most patients recovered in a few days, and no deaths were recorded. Interestingly, two patients (33.3%) with CDI did not show signs of diarrhea, and CDI testing in these patients was in response to the presence of fever of unknown origin. Of the fever episodes showing diarrheal complications, 19% (four of 21) had a diagnosis of CDI.
Table 2.
The details of the clinical course of six patients with CDI complicated with fever
| Case | Age,ya | Primary | Stage | Initial/Recurrence Therapy | Prior Anti‐Cancer Therapy | Days to CDI Treatment, db | Anti‐Bacterial Agent Used at CDI | Max WBC, /μL | Max CRP, mg/dL | Max Fever | Latency from fever, dayc | Latency From Diarrhea, dd | Complicated With Diarrhea | The Days Until Healing | Death due to CDIe | Treatment |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 39 | OC | IV | Initial | Dd‐TC 2 cycle | 10 | − | 4940 | 5.26 | 38.5 | 0 | 5 | + | 2 | − | Oral metronidazole |
| 2 | 34 | CC | IIA | Initial | RAH | 3 | + | 10 930 | 11.92 | 40 | 3 | − | − | 11 | − | Oral vancomycin |
| 3 | 54 | CC | IIA | Initial | CCRT | 45 | − | 21 600 | 11.3 | 39 | 1 | 1 | + | 2 | − | Oral vancomycin |
| 4 | 61 | EMCA | IIIA | Initial | TC 2 cycle | 14 | − | 5940 | 7.57 | 38.8 | − | 0 | + | 1 | − | None |
| 5 | 45 | CC | IIB | Recurrence | TC 6 cycle, dd‐TC 6 cycle | 17 | − | 3840 | 16.94 | 40.4 | 3 | − | − | 6 | − | Oral metronidazole |
| 6 | 64 | EMCA | IIIA | Initial | DC 6 cycle | 7 | − | 1570 | 3.32 | 38.5 | 0 | 2 | + | 1 | − | Oral metronidazole |
Abbreviations: CC, cervical cancer; CCRT, concurrent chemoradiotherapy; CDI, clostridium infection; CRP, C‐reactive protein; DC, docetaxel/carboplatin; dd‐TC, dose‐dense paclitaxel/carboplatin; OC, ovarian cancer; RAH, radical hysterectomy; TC, paclitaxel/carboplatin; WBC, white blood cell.
Age at diagnosis of Clostridium difficile infection.
Interval between the starting of anti‐cancer therapy and the development of clostridium infection treatment.
Interval between the starting of fever and the starting of clostridium infection treatment.
Interval between the starting of diarrhea and the starting of Clostridium difficile infection treatment.
Interval between the starting of treatment and the Clostridium difficile infection healing.
The occurrence of CDI did not show any association with age, primary disease, or cancer stage in patients. Four of the six patients contracted CDI following chemotherapy, one patient while in concurrent chemoradiotherapy, and one patient following radical hysterectomy. None of the patients developed CDI in follow‐up periods after finishing anticancer therapy. The chemotherapy administered prior to diagnosis of CDI was a combination of taxanes and platinum‐based agents. Although white blood cell levels increased in patients who contracted CDI after concurrent chemoradiotherapy or surgery, there was no increase of white blood cells in patients who contracted CDI after chemotherapy. All patients (except for one) received oral administration of vancomycin or metronidazole as treatment for CDI. However, the patient with the longest latency from fever to initiation of treatment required a treatment prolongation exceeding 5 days. Symptoms with diarrhea were confirmed earlier than high fever in three of four patients who were treated for CDI, and one was confirmed on the same day.
Overall, the number of patients with gynecological malignancies who developed CDI in our study cohort was eight, including two patients who showed fevers lower than 38.5°C. Overall, 75% (six of eight) of patients with CDI were complicated with fever 38.5°C or higher. The overall cumulative risk of CDI in all gynecological malignancy cases was 0.48% (eight of 1652) in patients admitted for anticancer therapy and 1.6% (eight of 485) in patients with gynecological malignancies. Two patients with fevers lower than 38.5°C also did not show recurrent CDI and were treated in hospital with no reported disease outbreak (Table 3). One of the two patients did not have diarrheal symptoms and was diagnosed with slight fever of unknown origin. The other patient showed signs of CDI following treatment with cisplatin and irinotecan.
Table 3.
The details of the clinical course of two patients with CDI without fever
| Case | Age, ya | Primary | Stage | Initial/Recurrence Therapy | Prior Anti‐Cancer Therapy | Days to CDI Treatment, db | Anti‐Bacterial Agent Used at CDI | Max WBC, /μL | Max CRP, mg/dL | Max Fever | Latency From Fever, dc | Latency From Diarrhea, dd | Complicated With Diarrhea | The Days Until Healinge | Death due to CDI | Treatment |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 50 | CC | IIIB | Initial therapy | CCRT | 9 | − | 9560 | 2.53 | 37.8 | − | − | − | 1 | − | Others |
| 2 | 57 | EMCA | IIB | Recurrence | TC 6 cycle, CDDP + irinotecan 6 cycle | 9 | − | 4490 | 1.11 | 37.8 | 1 | 4 | + | 1 | − | Oral metronidazole |
Abbreviations: CC, cervical cancer; CCRT, concurrent chemoradiotherapy; CDDP, cisplatin; CRP, C‐reactive protein; CDI, clostridium infection; TC, paclitaxel/carboplatin; WBC, white blood cell.
Age at diagnosis of Clostridium difficile infection.
Interval between the starting of anti‐cancer therapy and the development of clostridium infection treatment.
Interval between the starting of fever and the starting of Clostridium difficile infection treatment.
Interval between the starting of diarrhea and the starting of Clostridium difficile infection treatment.
Interval between the starting of diarrhea and the Clostridium difficile infection treatment.
Immunocompromised patients are at risk for developing CDI; however, only one patient (case 6, Table 2) had immunosuppressive grade 3 neutropenia. None of the CDI patients had a history of proton pump inhibitor use, another potential risk factor for CDI. Surprisingly, a history of antibiotic administration prior to CDI development was observed in only one of the eight CDI cases (case 2, Table 2). This patient developed a high fever after the 3‐day administration of the prophylactic antibiotic flomoxef sodium.
4. DISCUSSION
The incidence of CDI has increased 42.7%, and multiple recurrent CDI has also increased 188% in the western society from 2001 to 2012.18 Exact diagnosis of CDI is often difficult in some clinical situations.8 Previous studies often focus on the diarrheal symptoms associated with CDI. However, other symptoms of CDI, especially in gynecological cancer patients, have not been thoroughly investigated. The current study examined the potential of CDI in patients with gynecological malignancies who were running a fever. Overall, 9.5% of patients with a fever 38.5°C or higher were diagnosed with CDI. All patients with CDI had fevers 37.5°C or higher with the majority (six of eight) showing fever higher than 38.5°C. Overall, our findings showed that the risk of developing CDI needs to be considered in gynecological cancer patients.
There are numerous studies supporting the correlation between use of various antibiotics and development of CDI.5, 9, 19, 20 C difficile accounts for 15% to 20% of cases of antibiotic‐associated diarrhea, and its pathogenicity is attributed to the production of two major toxins—A and B.19, 20 Toxin B is several hundred‐fold more cytotoxic than toxin A, but only toxin B cytotoxicity is weak, toxin B easily penetrates into the cell because toxin A induces epithelial desquamation and increases mucosal permeability leading to increased fluid secretion, and potent cytotoxicity. Toxin B lacks significant intestinal toxicity but plays a major role in pathogenicity.21 CDI is usually diagnosed when clinical symptoms are present and the C difficile toxin test is positive in a fecal specimen. Instead of positive fecal toxin tests, findings of pseudomembranous enteritis may be confirmed with a colonoscopy.20
All antibiotics can enhance the risk of developing CDI.5 Additionally, proton pump inhibitor usage, advanced age, history of intensive care unit admission, insertion of nasal tube, postoperative period, compromised immunity, obesity, and cancer‐bearing are also known to enhance CDI risk.11, 20 Some studies report that CDI is associated with anticancer therapy especially in gynecological malignancy.15, 16 In our study cohort, seven of the eight patients underwent antibiotic treatment after developing a fever because the attending physicians decided to use antibiotics against infection of unknown origin. Infection work up, except for the CDI test prior to the administration of antibiotics, did not show any significant findings (data not shown). Therefore, CDI diagnosis was concluded in these seven patients. Only one (case 2, Table 2) of the eight patients developed CDI following antibiotic administration, and this same patient also had surgery (radical hysterectomy) prior to developing CDI. All other patients had undergone chemotherapy prior to the occurrence of CDI. There is evidence to suggest that anticancer treatments with chemotherapy or radiotherapy in cancer patients has the same CDI risk as antibiotic treatment, regardless of the presence or lack of immunosuppression7. Husain et al16 report a 2.2% risk of CDI in standard‐dose paclitaxel‐containing regimens, and as high as 20% in patients receiving high‐dose regimens. This enhanced CDI risk has been attributed to prolonged pancytopenia in combination with chemotherapy‐induced bowel damage and concurrent use of prophylactic antibiotics. Intestinal mucosal toxicity of representative cytotoxic agents including cisplatin or carboplatin has been ascertained.22 Examination of crypt cell production rate and the crypt‐villus ratio in mice revealed profoundly reduced integrity of intestinal mucosa upon cisplatin treatment, less so with carboplatin. A significant reduction in villus height was observed between days three and seven in cisplatin treated mice, and dexamethasone did not reverse or protect against these pathologic changes. CDI has been reported in 6.1% of patients who underwent cisplatin‐based chemotherapy in ovarian cancer.15 CDI was detected in two of the four patients who developed diarrhea following ovarian cancer chemotherapy during this 2‐year study. Neither of the CDI patients had been administered antibiotics prior to developing CDI, and both patients underwent recurrent CDI after the second course of treatment comprising cisplatin, adriamycin, and cyclophosphamide. CDI recurrence was not recorded after the third chemotherapy course wherein the treatment was changed from cisplatin to carboplatin. In a study investigating CDI in obstetrics and gynecology patients, James et al13 report 18 patients (0.02% of the study population) with documented CDI. Among the 18 patients, five were gynecologic oncology patients, two had received antibiotics for wound infection, two for urinary tract infections, and most other benign gynecology patients had received prophylactic antibiotics around surgery time. CDI has conventionally been thought to occur following antibiotic administration. Accordingly, CDI detection and diagnosis is often overlooked in cases where antibiotics have not been used.
Although it is generally known that CDI patients typically have a fever,10, 11, 12 the fact that this is not always complicated with diarrhea is not common knowledge.8, 9, 10, 11, 12 Of the eight CDI patients identified in our study, three patients did not show diarrhea, suggesting that diarrhea may not necessarily accompany CDI, even in gynecologic cancer patients. The CDI testing in these patients was prompted by the presence of fever of unknown origin. The diagnosis of CDI in two of these three cases was delayed; while it was not fatal, it did eventually take longer to cure. In contrast, there was a clear correlation between diarrhea and time to heal after the onset of treatment.23, 24 Calderwood et al24 described that a minority of CDI have the disease primarily in the cecum and right colon, presenting with marked leukocytosis and abdominal pain but little or no diarrhea. On the other hand, mild diarrhea is often associated with occasional abdominal cramps, which can be life threatening.16 Notably, it was reported that medical staff tended to be unaware of diarrhea in their own patients, and it was reported that half of the patients with CDI had symptoms of diarrhea that were overlooked by the attending physicians and were diagnosed by referencing the nurses' notes.25 In our study cohort, all patients suffering from CDI following chemotherapy had a normal level of white blood cells. Thus, our findings showed that a typical symptoms of CDI increased white blood cells that is not necessarily experienced during anticancer therapy, which makes diagnosis extremely difficult. Generally, fever is observed in about 30% of CDI patients. However, all eight CDI patients in our study exhibited fever suggesting that fever tends to occur with a higher frequency during anticancer treatment.
Figure 1 shows our proposed framework for the identification and management of CDI in cancer‐bearing fever patients. The CDI test must be considered regardless of a history of antibiotic usage. Patients who do not respond to antibiotics for the treatment of fever of unknown origin should also undergo the CDI test. On the other hand, infection work up is recommended for those patients who test positive for CDI and those who are not responding to metronidazole or vancomycin treatment. In our cohort, examination of risk factors for CDI in fever patients could not be achieved because the number of CDI events did not reach the level required for multivariate analysis.
Figure 1.
Guidelines for management of cancer bearing fever patient by considering Clostridium difficile infection
In conclusion, the present study shows that CDI does not always present with typical manifestations in cancer patients. It is important to rule out CDI in gynecological malignancy patients showing fever of unknown origin, regardless of gastrointestinal symptoms, and especially when there is no history of antibiotic use.
CONFLICT OF INTEREST
None of the authors have a conflict of interest.
AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, S.Y.; Methodology, S.Y., A.T.; Investigation, S.Y., A.T., M.F., S.O.; Formal Analysis, S.Y., S.O., S.T.; Resources, S.Y.; Writing ‐ Original Draft, S.Y.; Writing ‐ Review & Editing, S.Y.; Visualization, S.Y.; Supervision, M.K., H.K.
ACKNOWLEDGEMENT
The authors thank Phillip Suzuki, for critical comments and review of this manuscript.
Yanazume S, Tokudome A, Fukuda M, et al. Clostridium difficile infection in fever patients with gynecological malignancies. Cancer Reports. 2019;2:e1200. 10.1002/cnr2.1200
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