Clinical and Pathological Characteristics of Amoxicillin Associated Hemorrhagic Colitis

Background and objective: Amoxicillin is an antibiotic with various benets for patients. However, adverse reactionssometimes occur, and the clinical misdiagnosis rate is highbecause some clinicians have limited knowledge regarding this drug. Combined with literature review, this study explores the clinical pathological features of hemorrhagiccolitis caused by amoxicillin to improveits diagnosis and treatment. Methods: “Amoxicillin”, “hemorrhagiccolitis”, “antibioticassociated colitis (AAC) ”, “antibioticassociated hemorrhagic colitis (AAHC) ”were used as the index words to retrieve Pubmed, EMbase, Wanfang Database and Chinese national knowledge infrastructure (CNKI). Related articles were then selected and combined with thepatient information obtained from our department to complete the clinical pathological les.To summarize the clinicopathological data, diagnosis, treatmentof the disease. Results: A total of 19 articles were included in the study. Patients may have abdominal pain, bloody stools or blood in the stool, but generally no anemia.The laboratory tests for hemoglobin (HGB) and erythrocyte sedimentation rate (ESR) are normal, andC-reactive protein (CRP) is often elevated. Abdominal ultrasound and computed tomography (CT) ndings revealed that the intestinal wall wasthickened and presented edema, and some partsexhibited peritoneal effusion.Upper gastrointestinal endoscopy usually has no bleeding changes. A colonoscope was used to reveal the mucosal erosion, mainly found on the right hemicolon and this nding was consistent with acute colitis. The pathology is consistent with acute hemorrhagic colitis.The symptoms were relieved after drug withdrawal and principally with supportive treatment. The patient’s gastrointestinal symptoms usually did not recur. Conclusion: Patients with acute colitis caused by amoxicillingenerally experienced abdominal cramps and bloody stools, but treatment response was good, and follow-up monitoring revealed norecurrence. AAC:antibiotic associated colitis; AAHC:antibiotic associated hemorrhagic colitis; CNKI:Chinese national knowledge infrastructure; WBC:white blood cell count; HGB:The laboratory tests for hemoglobin; RBC: red blood cell count; ESR:erythrocyte sedimentation rate; CRP:C-reactive protein; CT:computed tomography; K. oxytoca:Klebsiella oxytoca; OB:occult blood; CDT:ADP-ribosyltransferase; AABD:antibiotic-associated bloody diarrhea.


Background
Amoxicillin plays a crucial role in disease prevention and has made important contributions totheprotection of human health, but related adverse reactions and complications have increasinglyoccurred 1, 2 , in which antibiotics associated colitis (AAC)is comparatively common without clear pathogenesis 3 . Antibiotics associated hemorrhagic colitis (AAHC) is a special type of AAC. After treatment with broad-spectrum antibacterial drugs such as uoroquinolone, cephalosporin or penicillin and etc. within two to seven days, AAHC appeared and the clinical manifestations were abdominal pain, diarrhea, and nally bloody stools 4 . Amoxicillin and other penicillin derivatives are the most common pathogenic drugs 5 .
Amoxicillin, also known as ampicillin and penicillin, which is a beta lactam antibiotic that mainly acts on gram-positive bacteriaand some gram-negative bacteria 6 . According to the reports by To eret al in 1978 7 and Sakuraiet al 8 in 1979, this antibiotic causes hemorrhagic colitis, and adverse reactions have been reported in many countries worldwide 4,[9][10][11][12][13] .Amoxicillin-clavulanate potassium is a combination of amoxicillin and the enzyme inhibitor clavulanate potassium, which can also cause hemorrhagic enteritis 14,15 . Given the lack of speci city and rapid change of the AAHC symptoms caused byamoxicillin, as well as the lack of cognition of the digestive system performance of AAHC in clinical work, early diagnosisis di cult and misdiagnosis often occurs, posing risks to patients.Therefore, this review analyzes the clinical features of AAHC in order to improve the diagnosis rate of it.

Literature Search strategy
The selected databases including PubMed, EMBASE, Wan Fang and Chinese National Knowledge Infrastructure(CNKI) databases were searched to select the suitable literature related to amoxicillin and related drugs induced hemorrhagic colitis.The search was began in setting up the literature database and ended in April 2019. The search strategy included the following terms: "amoxicillin", "amoxicillin clavulanate potassium", "hemorrhagic colitis", "antibiotic-associated hemorrhagic colitis". The search language was limited to English. Corresponding Chinese characters were used in Chinese database. On this basis, we tried to trace the references that had been incorporated into the literature and manually retrieve the relevant conference proceedings to identify potential informations that was not retrieved.
Unpublished literature was not retrieved.

Inclusion and exclusion criteria
Studies were included in this review if the following conditions were met:The patient was nally diagnosed with hemorrhagic colitis after treatment with amoxicillin oramoxicillin-related drugs and had detailed clinical and pathological data that could be extracted.Studies were excluded if other drugs that caused hemorrhagic colitis wereothers. Drug-induced diseases were eventually diagnosed as diseases other than hemorrhagic colitis. Studies on animals, human xenografts and cell lines were excluded.
Studies were excluded if they were review articles, summaries, systematic evaluations, the reader letters and so on. Repeated publications were also removed.

Data extraction
The following information was extracted from the literature: title, rst author names, the year of publication, country, symptoms and signs, accompanying symptoms and laboratory, gastrointestinal and imaging examinations, treatment plan and follow-up information, combined with the clinical data of one patient admitted to our department and clinical characteristics of the disease. All included literature was examined by two reviewers. If any differences arose, then the nal results decided through a discussion, or consultation with a third reviewer.

Results
Literature search results 19 articles were included in the study, and the basic characteristics of the included articles were shown in Table S1 and S2. All patients were treated with amoxicillin or amoxicillin-related drugs, and other gastrointestinal diseases were excluded from laboratory and imaging examinations, and the diagnosis was hemorrhagic colitis.

General information
2.1.1 Case report A 43-year-old female patient presented with yellow paste stool after oral administration of 200mg amoxicillin 5 days before admission due to the upper respiratory tract infection. Three dayslater, the patient was admitted to the hospital with acute abdominal pain, nausea, vomiting ,and 10 times bloody diarrhea. Physical examination revealed a temperature of 37.0℃, pulse of 66 beats/min, respiratory rate of 16/min and blood pressure 119/73 mmHg. Physical examination found that she had an acute painful face, slightly tense abdominal muscles, tenderness in the lower abdomen, but no rebound pain.
Auscultation bowel sounded3 times/min, but tone weakened. Other physical examinations did not show positive signs.After admission, blood routine examination: white blood cell count (WBC) 7.18 *10 9 , neutrophil value (NE,74%), red blood cell count (RBC) 5.14*10 12 , hemoglobin (HGB) 123 g/l, platelet count (PLT) 193*10 9 ;stool routine: fecal hemorrhage, RBC full eld of vision/HP, WBC+, occult blood (OB): positive (+). There were no obvious abnormalities in liver function, renal function, electrolyte, coagulation function and autoimmune disease antibody spectrum. High-sensitivity C-reactive protein (hsCRP) was patientpresented abdominal pain and diarrhea after oral amoxicillin, consistent with AAHC. Omeprazole was administered, andrehydration and compound glutamine were provided to promote intestinal mucosal repair. On the third day of admission, the patient was relieved of yellow and soft stool. On the fth day, the symptoms were completely relieved and the patient was discharged. Followup for 45 days after discharge showed no recurrence of abdominal pain or bloody stool. The colonoscopy results showed restoration to normal mucosal image (Figure5).

Case characteristics
In combination with our patient, 51 patients were analyzed, 27 males and 24 females. The age of onset was 5 -74 years, with an average of 35.3 years. The course of disease was 1-9 days, with an average of 3.9 days. No remarkable correlation existed between onset and age and gender. Amoxicillin was administered at a dose of 300-4500 mg/day. The most common cause of medication was upper respiratory tract infection (23cases, 45.1%), followed by eradicated Helicobacter pylori (7 cases), gingivitis (4 cases), tonsillitis (3 cases), acute appendicitis, acute otitis media, dog bites and other diseases. Thirty patients were taking other drugs at the same time, the most common of which were metronidazole (6 cases), acetaminophen (2 cases) and nonsteroidal antiin ammatory drugs (NSAIDs)(2 cases).

Signs and symptoms
Abdominal pain was the most common symptom, which were present in 48 cases (94.1%). The most common symptoms were followed by distended abdomen, accompanied by diarrhea,characterized byyellow and watery consistency with frequency reaching more than 10 times per day. The patients may have nausea and vomiting at the same time. All patients had bloody stools or blood in the stool (51 cases, 100%), with a frequency of up to 20 times per day. The patients may have abdominal tenderness, but no muscle tension or rebound tenderness. The patientsdid notpresent with jaundice or anemia. Rectal examination showed bright red blood. Four patients developed fever with a maximum body temperature of 38.5℃, which returned to normal after symptomatic treatment.

Abdominal imaging
Ultrasound examination revealed thickening of the intestinal wall and peritoneal effusion. Abdominal Xray showed thickening of the intestinal wall, dilatation of the intestine or accumulation of gas, and there was no remarkable change. Gas angiography suggested a colonic sputum and a jagged appearance of the descending colon. Abdominal CT showed intestinal wall edema, thickening, in ammatory changes and ascites.

gastrointestinal examination
Total colonoscopy and biopsy revealed mucosal hemorrhage changes mainly in the right colon,rectum and sigmoid colon are completely normal.Microscopic appearance of mucosal erosion, hemorrhage, edema, and even active bleeding were found. Some patients showed ulcerative lesions and intestinal stula. No remarkable changes in the colonoscopy lesions were found after 2-3 days of illness, but the colonoscopy lesions disappeared completely after one week.The intestinal mucosa returned to normal. Upper gastrointestinal endoscopy could be normal or showed in ammatory changes without evident hemorrhagic lesions.

Pathology
The disease was consistent with acute hemorrhagic colitis. Mucosal congestion and edema were observed. In ammatory cells such as monocytes, neutrophils and lymphocytes in ltrated in the lamina propria, and red blood cells in ltrated in the interstitial. However, the gland or crypt structure showed nochanges.

Treatment and follow-up results
The treatment principle was to stop the original oral medication, and the symptoms were relieved quickly after the medication was stopped.The main treatment for acute diarrhea was supportive treatment with focus is on rehydration and correction of electrolyte imbalance. In severe cases, intravenous short-term steroid therapy could be used. Most patients recovered quickly, with complete remission in the short term, and no complications. Gastrointestinal symptoms did not recur in patients after followup after discharge.

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The intestinal tract is one of the common target organs for drug damage 16 . Drug-related hemorrhagic colitis is categorized into AAHC and other drug-related hemorrhagic colitis; and 85% ofAAHCiscaused byamoxicillin or other penicillin derivatives 17 . Most cases of amoxicillin-induced hemorrhagic colitis, including clinical characteristics, occur within one to nine days of medication and can occur at all ages [18][19][20] .The history of taking amoxicillin or penicillin derivatives.Patients have bloody diarrhea, or bloody stool, with or without abdominal cramps, and other systems are rarely involved. Colonic mucosa microscopically demonstrates mild to moderate in ammatory changes,probably associated with ulcer, mucosal edema, and bleeding 21 . It is mainly located in the right hemicolon or transverse colon with segmental distribution 22 , similar to ischemic colitis 3 . Pathological examination revealed erythrocyte in ltration of the colonic mucosa.
KatoSet al 18 regarded that colonoscopy con rms AAHC is safe and effective,whereas HogenauerCet al 22 claimed that sigmoidoscopy aloneis ineffective, and colonoscopy is necessary for the diagnosis of AAHC. However, Yamada Met al 19 thought that AAHC patients demonstrated remarkably improved symptoms after drug withdrawal and without implementation of invasive examination.Those who are quali ed for colonoscopy are recommended to actively improve the examination. Ultrasound examination can probably provide clues for the diagnosis of AAHC and reduce the need for invasive examination 23 . The abdominal CT of the patients showed diffused edema of the intestinal wall with partial ascites, which should be differentiated from pseudomembranous colitis 23 . If colonoscopy cannot be tolerated by the patients and X-ray andCTexaminationsare inappropriate, then abdominal ultrasound may be feasible.
In the identi cation of diseases including pseudomembranous colitis or clostridium di cile-associated diarrhea, infectious colitis, necrotizingenterocolitis, ischemic colitis, in ammatory bowel disease, allergic purpura, hemolytic uremic syndromeand other drug-related colitis 18,25 ,some patients conform to AAHC in the short term, but eventually diagnosed with other diseases,should pay attention to the identi cation of other diseases 26 .
The cause of AAHC has not been fully elucidated. In 1982, DickinsonRJet al 11 discovered that the infection morbidity of most patients were caused by the drug, and the respiratory pathogens and drugs were speculated to interact with each other in a similar hypersensitivity reaction. However, approximately 50%morbidity due to respiratory tract infection was not caused by the drugs and the possibility is not thigh. Antibiotic intake results in ora imbalance, which increases theamount of carbohydrates that cannot be metabolized; hence,diarrhea occursdue to the in ltration of carbohydrates 27 . This inference may explain diarrhea in patients, but cannot explain hemorrhage. Antigen-antibody responses damage the integrity of vascular endothelium, leading to submucosal hemorrhage in the intestinal wall. Drugs can also directly or indirectly damage endothelial cells, leading to thrombosis, erythrocyte aggregation, and colonic hemorrhage 28 .
It is speculated that the bacterial infection may be related to AAHC, and the patient develops bacterial infection and then AAHC. K.oxytocais probably the most common pathogenic bacteria of AAHC 10,19 . It is found in the intestinal tract of 1.6-10% of healthy people 19,29 . Zollner-SchwetzI et al 30 regarded thatK.oxytocais not a pathogenic factor of hemorrhagic non-hemorrhagic antibiotic associated diarrhea, but ChengVC et al 31 claimed that patients with K.oxytoca present only antibiotic-associated diarrhea and nothemorrhagic colitis. Given the prevalence of AAHC symptoms, the missed diagnosis or misdiagnosis rate ofK.oxytocainfection is high 19 . However, the pathogenic mechanism of K.oxytocaremains unknown, speculating that the overgrowth of bacteria was caused by the drug treatment 32,33 . Flora-produced matter is closely related to the occurrence of disease 29 . K.oxytoca-producedcytotoxicities that damage the intestinal epithelial cells 34 , include nonribosomal peptides tilivalline and tilimycin 35 43,44 . In addition, AAHC may also be associated with clostridium perfringens infection 45 .
AAHC is self-limiting, and its treatment should be discontinued rst, with supportive treatment as the main method, focusing on uid rehydration and electrolyte correction 46 .In severe cases, short course intravenous hormone therapy is available. Moreover, theuse of probiotics may be abene cial treatment 47 , in which most of the patients recovered quickly with complete remission in a short time, and without complications.

Declarations
Ethics approval and consent to participate This article does not contain any studies with human or animalsubjects.

Consent for publication
Written informed consent for publication was obtained from all participants.

Availability of data and materials
The datasets used and analysed during the current study available from the corresponding author on reasonable request.   Enteroscopy was diagnosed as hemorrhagic colitis (Figure3).