A Clinical Investigation into the Long-term Use and Safety of Killed Escherichia coli Suspension-Hydrocortisone Combination Ointment for the Treatment of Hemorrhoids

Abstract

Objectives:

Conservative treatment for hemorrhoids may be long-term, but there are only a few studies that have reported on the long-term use of corticosteroid-containing preparations. Therefore, the aim of this study was to conduct a clinical investigation into the long-term use and safety of Killed Escherichia coli suspension-hydrocortisone combination ointment for the treatment of hemorrhoids.

Methods:

A review of 578 hemorrhoid patients who experienced an adverse reaction to Killed Escherichia coli suspension-hydrocortisone combination ointment at Coloproctology Center Takano Hospital between June 2019 and December 2019 was conducted.

Results:

Of the 578 patients included in the analysis, 430 patients (74.4%) had internal hemorrhoids and the median duration from the date of initial diagnosis was 0.70 months. The median prescription period of patients treated with Killed Escherichia coli suspension-hydrocortisone combination ointment was 20 days, and no adverse reactions were observed. When the prescription period of patients treated with Killed Escherichia coli suspension-hydrocortisone combination ointment was categorized into a within 30-day period (n=332), a 31-90-day period (n=63), and a ≥91-day period (n=23), the median disease duration at initial diagnosis was 0.46 months, 1.00 months, and 8.00 months, respectively. These findings indicate that the prescription period tended to be longer as the disease duration increased.

Conclusions:

In this study, the onset of adverse reactions to the use of Killed Escherichia coli suspension-hydrocortisone combination ointment in the treatment of hemorrhoids could not be confirmed. Further studies to investigate the safety of the long-term use of this treatment needs to be conducted.

Introduction

Conservative treatment or surgical intervention is selected for the treatment of hemorrhoids according to its degree of seriousness. In conservative treatment, pharmacotherapy is carried out with the aim of improving the patient's quality of life, and is effective for relieving such symptoms as swelling, prolapse, pain, and hemorrhaging. The long-term use of corticosteroid-containing preparations in conservative treatment is a safety-concern among healthcare professionals because the duration period of treatment is prolonged in chronic hemorrhoid cases[1].

Many of the local side effects caused by topical corticosteroids are the result of long-term continuous use of steroidal anti-inflammatory agents over the strong class and the occlusive dressing technique (ODT) over the medium class, and are more likely to occur in the intertriginous areas such as the pudendal region, perianal region, or axilla[2]. Moreover, concomitant perianal steroidal dermatitis and perianal tinea infections for the treatment of hemorrhoids can be observed with the long-term use of corticosteroid-containing preparations[3].

An ointment consisting of 0.163 ml of Killed Escherichia coli suspension and 2.5 mg of hydrocortisone (Posterisan^Ⓡ forte ointment) has been widely used in clinical practice for many years as medication for the treatment of hemorrhoids and anal fissures because it provides a protective effect for local infections, a granulation promoting effect, and an anti-inflammatory effect based on the synergistic relationship between the two active pharmaceutical ingredients[4]. However, only case reports provide evidence for the long-term use of this Killed Escherichia coli-hydrocortisone combination ointment. Therefore, objective data on the safety of the long-term use of this ointment needs to be collected and analyzed.

In this study, we retrospectively collected clinical data from patients who experienced an adverse reaction to Killed Escherichia coli-hydrocortisone combination ointment and looked at the occurrence and onset of these adverse reactions according to the length of the prescription period.

Methods

The onset of adverse reactions due to the Killed Escherichia coli-hydrocortisone combination ointment was confirmed from patient medical records and tabulated according to the length of the prescription period.

Subjects

A total of 578 patients (213 male; 365 female) visited Coloproctology Center Takano Hospital between June 2019 and December 2019 to receive curative treatment for hemorrhoids. Patients who met the inclusion criteria were enrolled in this study and those who did not meet the inclusion criteria were excluded from the study.

(1) Inclusion criteria

Patients who were diagnosed with hemorrhoids and prescribed the Killed Escherichia coli-hydrocortisone combination ointment as treatment for hemorrhoids from their first visit.

(2) Exclusion criteria

Patients who underwent surgery for anal disease during the observation period.

(3) Discontinuation criteria

When patients expressed a desire to no longer participate in the study.

Research ethics

The researchers for this study were approved by the Ethics Review Committee of Coloproctology Center Takano Hospital (Committee No. 11000070) on September 2^nd, 2020. We also made an announcement on the University Hospital Health Information Network (UMIN-CTR) prior to the start of the study (ID: UMIN000041960). This study was conducted in compliance with the Ethical Guidelines for Medical Research on Human Subjects and the ethical principles and research protocol based on the Declaration of Helsinki. Informed consent was obtained using an “opt-out” method under the approved the ethics committee.

Data for this study was obtained from past medical records. The outline of the research was posted in the hospital and on the hospital website and updated regularly. The data from patients who declined either verbally or in writing were not used in this study.

Clinical factors of observation

The period from the date patients were first diagnosed with having hemorrhoids and prescribed the Killed Escherichia coli-hydrocortisone combination ointment to the start of the study (October 1, 2020). Moreover, the date at first diagnosis, age, type of hemorrhoids, duration of the disease, dosage, the length of the prescription period using the drug under investigation (the period until the onset of an adverse reaction to the drug), the name of the concomitant drug (including dosage), the presence of comorbidities, the presence of adverse events for which a negative causal relationship could not be ruled out, and the side effects were the clinical factors investigated.

Statistical analysis

The clinical factors were tabulated to calculate the incidence of adverse reactions according to the length of the prescription period patients used the Killed Escherichia coli-hydrocortisone combination ointment. The IBM Statistical Package for the Social Sciences (SPSS) software version 25.0 (IBM Corp, Armonk, New York, USA) was used to analyze the data.

Results

Patients

All of the data for the 578 patients enrolled in this study were included in the analysis.

Clinical factors

The clinical factors of the patients are shown in Table 1. The average age was 46.7 years. Patients in their 30s accounted for the highest proportion of the sample population at 22.3%, followed by patients in their 40s at 20.2%. There were more females (365) than males (213). The majority of the male patients were in their 40s (23.5%) and the majority of the female patients were in their 30s (26.8%).

Table 1.

Study Population Characteristics.

Number of subjects included in the analysis	N		578
Age	Mean ± SD		46.7±18.3
Sex	N (%)	Male	213 (36.9)
		Female	365 (63.1)
Type of hemorrhoids (as of the date of initial diagnosis)	N (%)	Internal hemorrhoids*	430 (74.4)
		Grade I	99 (17.1)
		Grade II	203 (35.1)
		Grade III	115 (19.9)
		Grade IV	5 (0.9)
		Unknown	1 (0.2)
		Incarcerated hemorrhoids	11 (1.9)
		External hemorrhoids	1 (0.2)
		Thrombosed external hemorrhoids	135 (23.4)
		Unknown	1 (0.2)
Disease duration, months (N=418)	Median (min, max)		0.70 (0.03, 480.00)
Comorbidity	N (%)	None	417 (72.1)
		Present	161 (27.9)
Time period and date of prescription	Median (min, max)		20.0 (3.0, 423.0)
Dosage	N (%)	2 g once/day	327 (56.6)
		2 g twice daily	194 (33.6)
		As needed	57 (9.9)
Concomitant medications for the treatment of hemorrhoids	N (%)	None	375 (64.9)
		Present	203 (35.1)

*: Internal hemorrhoids are classified according to the Goligher classification, with a breakdown of each grade of severity.

The most common type of hemorrhoids was internal hemorrhoids and they were found in 430 of the patients (74.4%). The severity of the internal hemorrhoids was most commonly identified as Grade II (35.1%) on the Goligher classification. The median duration period from the time patients were first diagnosed as having hemorrhoids to cure was 0.7 months with a maximum period of 480 months (40 years). A total of 161 patients (27.9%) experienced comorbidities. The main comorbidities were hypertension (92 patients; 15.9%), hyperlipidemia (43 patients; 7.4%), diabetes (19 patients; 3.3%), prostatic hyperplasia (8 patients; 1.4%), angina (7 patients; 1.2%), dyslipidemia (6 patients;1.0%), and cerebral infarction (6 patients; 1.0%).

The dosage of the Killed Escherichia coli-hydrocortisone combination ointment was 2 g once per day in 327 patients (56.6%), 2 g twice per day in 194 patients (33.6%), and 2 g per day as-needed in 57 patients (9.9%).

The median prescription period using the Killed Escherichia coli-hydrocortisone combination ointment was 20 days with a maximum period of 423 days. The prescription period was within a 30-day period for the majority of the patients (456 patients; 78.9%), a 31-90-day period for 87 patients (15.1%), and a ≥91-day period for 35 patients (6.0%).

Concomitant medication was used to treat hemorrhoids in 203 patients (35.1%). The major concomitant medications used were oral magnesium oxide (103 patients; 17.8%), oral bromelain/tocopherol acetate (98 patients: 17.0%), and oral loxoprofen sodium (25 patients; 4.3%).

Cross-tabulation results of the clinical factors

Table 2 summarizes the duration of hemorrhoids in males and females. The median (min, max) was 0.25 (0.03, 360.00) months for males and 1.00 (0.03, 480.00) months for females, with a longer disease duration period observed in females.

Table 2.

The Duration of Hemorrhoids (Males and Females).

	(N=418)	Male	Female
Duration of hemorrhoids (as of date of first presentation)	N	151	267
(Months)	Median	0.25	1
	(min, max)	(0.03, 360.00)	(0.03, 480.00)

Table 3 summarizes 288 cases of internal hemorrhoids for which the duration of hemorrhoids at the time of initial diagnosis could be confirmed by severity (Goligher classification). The median (min, max) duration of hemorrhoids from the first visit was 0.70 (0.03, 480.00) months for Grade I (n=55), 2.00 (0.03, 456.00) months for Grade II (n=152), 3.00 (0.03, 360.00) months for Grade III (n=77), and 7.50 (0.20, 120.00) months for Grade IV (n=4).

Table 3.

The Duration of Hemorrhoids (Severity of Internal Hemorrhoids).

	(N=288)	Grade I*	Grade II*	Grade III*	Grade IV*
Duration of hemorrhoids (as of date of first presentation)	N	55	152	77	4
(Months)	Median	0.7	2	3	7.5
	(min, max)	(0.03, 480.00)	(0.03, 456.00)	(0.03, 360.00)	(0.20, 120.00)

*: Internal hemorrhoids are classified according to the Goligher classification.

The prescription period using the Killed Escherichia coli-hydrocortisone combination ointment for 418 cases in which the disease duration of hemorrhoids at the time of initial diagnosis could be confirmed, was classified into a within 30-day period (n=332), a 31-90-day period (n=63), and a ≥91-day period (n=23). See Table 4. The median (min, max) disease duration at initial presentation was 0.46 (0.03, 480.00) months, 1.00 (0.03, 360.00) months, and 8.00 (0.1, 360.00) months, respectively.

Table 4.

The Duration of Hemorrhoids (Prescription Period of the Hemorrhoid Medication).

	(N=418)	Within 30 days*	31-90 days*	≥91 days*
Duration of hemorrhoids (as of date of first presentation)	N	332	63	23
(Months)	Median	0.46	1	8
	(min, max)	(0.03, 480.00)	(0.03, 360.00)	(0.10, 360.00)

*: The prescription period of the Killed Escherichia coli-hydrocortisone combination ointment.

Incidence of adverse reactions

No adverse reactions were observed in any of the 578 patients included in the analysis. One patient experienced swelling in the affected area, but when it was thoroughly inspected it was found that the swelling was due to the disease condition and a causal relationship with the medication was ruled out.

Discussion

In this study, we retrospectively collected data on the incidences of adverse reactions from the medical records of 578 patients who were prescribed the Killed Escherichia coli-hydrocortisone combination ointment and ascertained the incidences of adverse reactions according to the length of the prescription period. No side effects were observed. However, the electronic attachment includes the following important adverse reactions, glaucoma and posterior subcapsular cataract, and other adverse reactions that include hypersensitivity (i.e. contact dermatitis), skin infections, eye disorders (i.e. retinopathy and exophthalmos), and pituitary/adrenocortical system depression[5]. Therefore, it is important to keep in mind that when carrying out medical treatment that there is a possibility that patients may experience local and systemic side effects.

Of the 578 patients who were prescribed the Killed Escherichia coli-hydrocortisone combination ointment, 430 (74.4%) patients had internal hemorrhoids, and of these internal hemorrhoid patients the most common degree of severity was identified as Grade II (35.1%) on the Goligher classification.

The exclusion criteria for this study were patients who underwent surgery for anal disease during the observation period, so the proportion of patients with a high severity of internal hemorrhoids was low. Approximately 80% of the patients were in the within 30-day prescription period. The dose of the Killed Escherichia coli-hydrocortisone combination ointment are described in the electronic attachment where an appropriate amount of the ointment is usually applied or injected one to three times a day. Approximately 90% of these patients were prescribed treatment within the dosage and administration range, as specified in the electronic attachment, and the drug was considered to be appropriately used (including the as-needed prescription group). On the other hand, 87 cases (15.1%) with a 31-90-day prescription period and 35 cases (6.1%) with a 91-day or more prescription period were identified. Cases of long-term use were assumed to be due to the severity of the disease and the clinical factors of the patients. In previous reports, there were only 10 cases (35-70 days) in 2 studies where patients were treated over a period of more than 30 days, but in this study 122 cases were collected[6,7]. In the current study, there was a trend indicating that the longer the median disease duration at initial presentation was the longer the prescription period became. No adverse reactions were observed in patients with a prescription period of more than 30 days. However, it should be noted that long-term continuous use should be avoided in the electronic attachment, and long-term continuous use may cause symptoms similar to those associated with systemic corticosteroids. Safe long-term use of hemorrhoid treatment can be offered to patients if prudent follow-up is done.

The disease term to medical examination was longer in females than in males, and the disease time to medical examination was longer as the degree of seriousness of the internal hemorrhoids was higher. The results of gender are presumed to be a reflection of females being more reluctant to seek medical treatment due to embarrassment. With regards to the severity of internal hemorrhoids, it is often a result of patients trying to tolerate the symptoms which prolongs the duration and increases the severity of the disease. It is therefore important to destigmatize hemorrhoids and promote the treatment of this condition using effective hemorrhoid medication so that patients can receive quick medical intervention.

Based on the above findings, there were no adverse reactions caused by the Killed Escherichia coli-hydrocortisone combination ointment, but follow-up of patients should be carried out with continued attention to the proper use of hemorrhoid medication. Further studies to examine the safety of long-term continuous use of the Killed Escherichia coli-hydrocortisone combination ointment in a larger sample size is needed.

Conflicts of Interest

This survey was conducted with funding from Maruho Co., Ltd. Shota Takano, Kosuke Sugimoto, Yasushi Nakamura, Yasue Irei, Hirotaka Hamada, and Yoriyuki Tsuji have no conflicts of interest. Yoshinobu Kikukawa is an employee at Maruho Co., Ltd.

Author Contributions

Shota Takano: concept; drafting of the text; and responsible for overall content. Kosuke Sugimoto, Yoshinobu Kikukawa, Yasushi Nakamura, Yasue Irei, Hirotaka Hamada, and Yoriyuki Tsuji were involved in the drafting of the article. All authors reviewed and approved the final document for publication.

Approval by Institutional Review Board (IRB)

・Approval code: No. 11000070

・Name of the institution: the Ethics Review Committee of Coloproctology Center Takano Hospital

Disclaimer

Shota Takano is one of the Associate Editors of the Journal of the Anus, Rectum and Colon and on the journal's Editorial Board. He was in no way involved in the editorial evaluation or decision to accept this article for publication.

Trial Registration Number

(ID: UMIN000041960)