Typhoid intestinal perforation

　　I. Etiology

　　The typhoid bacillus only resides in humans and becomes the source of infection for this disease. People become infected by consuming contaminated water or food, or by directly or indirectly contacting the feces of patients and carriers. Intestinal typhoid perforation is one of the serious complications of typhoid fever.

　　II. Pathogenesis

　　1. Pathogenesis:Most of the typhoid bacilli entering the digestive tract through contaminated water or food are killed by gastric acid. When the number of bacteria entering the body exceeds 100,000, or when certain diseases cause a decrease in gastric acid, some typhoid bacilli may survive. The typhoid bacilli that have not been killed by the gastric acid barrier enter the small intestine, penetrate the epithelial cells of the small intestinal mucosa or cell gaps, and invade the intestinal wall lymphatic tissue, where they are engulfed by phagocytes and reproduce and proliferate. Some bacteria enter the mesenteric lymph nodes through lymphatic vessels, proliferate in large numbers, and enter the blood through the thoracic duct, causing septicemia. The typhoid bacilli enter various organs of the body, such as the liver, spleen, kidneys, gallbladder, etc., and reproduce there. The bacteria that are engulfed by phagocytes re-enter the blood, causing a second septicemia, activating sensitized lymphocytes and producing a strong delayed hypersensitivity reaction. The endotoxins released by the disintegration of bacteria can stimulate tissue cells to produce an inflammatory response, releasing various inflammatory mediators, such as tumor necrosis factor (TNF), interleukin 1 (IL-1), interleukin 6 (IL-6), platelet-activating factor (PAF), etc., causing changes in acute inflammatory tissue. Severe inflammatory reactions and infiltration of monocytes can cause necrosis, desquamation, and ulceration of the intestinal mucosa. Lesions involving blood vessels can cause intestinal bleeding. Ulcers that invade the muscular and serosal layers of the intestinal wall can cause intestinal perforation.

　　2. Pathology:The pathological changes of enteric typhoid mainly occur in the distal ileum within 100 cm from the ileocecal valve. The aggregated lymph nodes swell due to congestion, edema, and proliferation, and ulcers appear on the intestinal wall as the lymphoid aggregates necrose and fall off. Ulcers that invade blood vessels can cause intestinal bleeding. When the ulcers reach the muscular and serosal layers, they are prone to cause acute perforation if the intraluminal pressure increases or intestinal peristalsis is excessive. Based on clinical manifestations and pathological characteristics, the pathological process of enteric typhoid can be divided into four stages: proliferative phase, necrotic phase, ulcerative phase, and healing phase.

　　(1) Proliferative phase: The first week of the disease course. The lymph nodes in the intestinal wall become congested and edematous, with a large number of macrophages proliferating, and the lymphocytes become明显 swollen. After being engulfed by monocytes-macrophages, most of the typhoid bacilli continue to reproduce within the cells and are disseminated throughout the body with the lymphocytes and monocytes. At this stage, typhoid bacilli and toxins continuously enter the blood, causing systemic symptoms.

　　(2) Necrotic phase: The second week of the disease course. Due to the action of bacterial toxins and the excessive proliferation of macrophages compressing blood vessels, local ischemia occurs, leading to small focal necrosis in the swollen intestinal wall lymphatic tissue, which then merges and expands into a patchy shape.

　　(3) Ulcerative stage: the 3rd week of the course. Necrosis and desquamation occur in the submucosal lymphoid aggregates of the intestinal wall, forming elliptical ulcers along the long axis of the lymphoid aggregates and parallel to the long axis of the intestinal tract. Ulcers are usually located on the opposite side of the mesentery, with varying depths, generally reaching the submucosal layer, but some can extend to the muscular layer, even involving the serosa.

　　(4) Healing stage: the 4th week of the course. After ulcer formation, new granulation tissue appears in the submucosal layer and is covered by the regenerating intestinal mucosal epithelium to heal.

　　In the 3rd week of the course, the ulcerative stage, the small intestine is prone to perforation at the center of inflammation infiltration in the elliptical ulcer. According to statistics, about 90% of perforations occur within 100cm from the ileocecal valve, but there are also individual cases where perforation occurs in the jejunum, appendix, cecum, and other places. Most enteric typhoid perforations are solitary, with a diameter of 0.5～1.0cm, about 10% of patients have 2～4 perforation sites, and a few can reach more than 10. In some cases with solitary perforation, the ulceration of the intestinal wall may be so thin that it forms an impending perforation. Since enteric typhoid rarely causes peritoneal reaction and adhesion, perforation often leads to diffuse peritonitis, which is rarely contained or localized or forms an internal fistula. There may be a lot of free fluid in the abdominal cavity, and abscesses may form in the lower right abdomen or pelvis.

　　Typhoid enteric perforation can be complicated by uncontrollable massive intestinal hemorrhage.

　　Enteric ischemia refers to the obstruction of blood vessels supplying intestinal blood due to some cause, resulting in a decrease or loss of blood supply to the intestines, which cannot meet the physiological needs of the intestines. The intestinal wall may suffer from congestion, edema, or ulceration, and in severe cases, necrosis, hemorrhage, perforation, and peritonitis may occur. In diseases such as结节性多动脉炎 systemic lupus erythematosus, when the small intestinal arteries are involved, it leads to poor blood supply to the corresponding intestinal segments and the appearance of ischemic changes.

　　Perforation of enteric typhoid fever often occurs with typhoid fever in summer and autumn. According to statistics, the incidence of enteric perforation in typhoid fever is generally about 5%, with 60%～70% of perforations occurring within the 2nd or 3rd week of the course, 10%～20% in the 1st week, and a few occurring in the 4th week or later. Typical clinical manifestations include:

　　I. Symptoms of typhoid fever:Typical enteric typhoid fever is characterized by persistent high fever, abdominal pain, constipation or diarrhea, enlargement of the liver and spleen, relative bradycardia, and decreased white blood cells. The typical clinical course can be divided into 5 stages, namely:

　　1. Incubation period:From 3 to 60 days, usually 8～14 days. The length of the incubation period varies with the size of the infective dose and the strength of the body's immune ability. The incubation period is short for those with a large number of bacteria, strong virulence, and low body immune function. For waterborne infections, the intake of bacteria is less, and the incubation period is longer.

　　2. Early stage:It is equivalent to the 1st week of the course of the disease. The onset is usually insidious, with the earliest symptom being fever, with the body temperature rising stepwise to 39℃～40℃ within 5～9 days, often accompanied by general discomfort, aversion to cold, muscle pain, decreased appetite, abdominal distension, constipation or mild diarrhea, sore throat, cough, and other symptoms.

　　3, Acute stage:Corresponds to the 2nd to 3rd week of the course of the disease. Typical typhoid manifestations often occur. During this period, about 5% of patients may have intestinal perforation or intestinal hemorrhage.

　　① High fever: It usually presents as a persistent fever pattern, with high fever lasting without subsidence, especially common in drug-resistant typhoid patients. A few patients may present with a remittent fever pattern or irregular pattern, with fever lasting for 10-14 days.

　　② Relative bradycardia: Typhoid patients may have relative bradycardia when the body temperature is between 38℃ and 39℃, which is one of the representative manifestations of typhoid patients. In healthy people, the pulse rate also increases correspondingly with the rise in body temperature, usually estimated by a simple method that for every 1℃ increase in body temperature, the pulse rate increases by 10 beats per minute.

　　③ Gastrointestinal symptoms: Typhoid patients may have what is called typhoid tongue, characterized by red tongue body, thick and greasy fur, without fur on the tip and edge of the tongue, resembling a plum. Accompanied by anorexia, there may be abdominal discomfort or distension, mild tenderness in the lower right abdomen, and severe cases may have intestinal paralysis. Most patients complain of constipation, and some may have diarrhea, with stools 2-3 times a day, yellow-green or brownish, with a foul smell.

　　④ Neurological symptoms: By the end of the 1st week of onset, patients often have apathetic and slow responses, and may have symptoms of fatigue and poisoning, with tinnitus and decreased hearing in most cases. Most patients have persistent fever, and the above symptoms gradually worsen. In the 2nd week of fever, the neurological symptoms of the patient worsen, to the extent that they are not interested in the surrounding environment, experience confusion, restlessness, and insomnia. Severe cases may have delirium, coma, or appear with meningeal irritation signs.

　　⑤玫瑰疹: After the 1st week of the course of the disease, patients may have pale red, slightly raised rash on the shoulders, chest, abdomen, and back in batches, with a diameter of 2-4mm, which fades when pressed. The number is generally less than 10, and most of them subside within 2-3 days. Due to the light color, few number, and short duration of the rash, it is often easily overlooked.

　　⑥ Liver and spleen enlargement: 40% to 70% of patients may have liver and spleen enlargement starting from the 2nd week of the course of the disease, with soft texture and mild tenderness, and liver function abnormalities may occur. Jaundice may appear, and in patients with significant changes in liver function, the possibility of toxic hepatitis should be considered.

　　4, Remission period:Corresponds to the 4th week of the course of the disease. Starting from the end of the 3rd week, the body temperature gradually decreases to normal after the 4th week. The condition begins to improve, showing a remittent fever pattern of body temperature. It gradually decreases, and various symptoms gradually subside, appetite improves.

　　5, Recovery period:Around the 5th week of the course of the disease, the recovery period begins. Clinical symptoms appear before the pathological recovery. The patient's body temperature returns to normal, symptoms gradually subside or disappear, appetite increases significantly, and a feeling of hunger may occur. There may be sweating. In addition to the above typical onset form, some patients have atypical manifestations. Some start with pneumonia, showing sepsis symptoms on the 1st to 2nd day of onset, with symptoms and signs of lobar pneumonia, and the typhoid bacillus may be found in the sputum. Some start with arthritis, similar to the early stage of rheumatic fever. Some may start with pleurisy, typhoid nephritis, cholecystitis, or severe jaundice.

　　2. Symptoms of enteric fever perforation:Perforation is the most serious complication of typhoid fever, often occurring in the 2nd to 3rd week after the onset of symptoms, and it often occurs in patients with severe abdominal pain, distension, and tenderness. Some may occur a few days after treatment, when the patient has begun to improve and suddenly develops perforation. After perforation, the patient reports pain in the lower right abdomen, accompanied by nausea, vomiting, rapid pulse, cold sweat, and a temporary drop in body temperature (shock phase). After 1 to 2 hours, abdominal pain and other symptoms may slightly alleviate (calm phase). Soon, the patient develops persistent abdominal pain, appears in pain, and the body temperature rises rapidly again. Physical examination reveals symptoms of peritonitis throughout the abdomen, still prominently in the lower right abdomen, with generalized tenderness, rebound tenderness, muscle tension, and reduced or disappeared liver dullness.

　　The number, size, and depth of ulcers in enteric fever do not necessarily correspond to the severity of typhoid symptoms. Before the occurrence of perforation of enteric fever, some patients may experience prodromal symptoms such as gastrointestinal bleeding and abdominal dull pain. Some patients may become weak and dull due to long-term bed rest, and they may not necessarily have discomfort from abdominal distension until the perforation occurs, and then the pain in the abdomen gradually increases. There is also a less common type of typhoid fever patient with mild fever, headache, general malaise, limb ache, and decreased appetite, but the symptoms are mild, and they can still carry on with normal activities and work. By the time they come to the hospital, perforation has already occurred, which is called atypical typhoid fever. Perforation in atypical enteric fever patients is often misdiagnosed as appendicitis or appendiceal perforation. Some patients have a history of taking laxatives, undergoing barium enema, or irregular diet before perforation.

　　The diagnosis of perforation of enteric fever is often influenced by various factors. Most patients seek medical attention late, the perforation time is long, and there are severe symptoms of peritonitis, with obvious toxic symptoms or even toxic shock, and the reaction is relatively dull. Due to the influence of mental factors, patients often cannot clearly describe their condition, and during physical examination, only mild abdominal wall tenderness and mild muscle tension are found, making it difficult to make a diagnosis of typhoid fever. The signs in the lower right abdomen of atypical typhoid fever are often easily confused with acute appendicitis, and the symptoms and signs of perforation are atypical.

　　1. Understand the medical history before perforation:It is relatively easy to diagnose perforation of enteric fever when it is confirmed as enteric fever and peritonitis occurs during the process of diagnosis and treatment. Conversely, further investigation is needed.

　　(1) Whether living in an epidemic area and having a history of contact with typhoid fever.

　　(2) Consider the possibility of enteric fever when there is unexplained persistent fever (38℃～40℃) accompanied by headache, loss of appetite, abdominal distension, colic, and diarrhea.

　　(3) Whether it has characteristic clinical manifestations of typhoid fever and specific laboratory findings, such as a low white blood cell count and a positive Widal reaction.

　　2、剖腹探查诊断：Laparoscopic exploration for diagnosis:

　　How to prevent typhoid perforation of the intestinal tract

　　1. When typhoid patients receive surgical treatment, they are at the peak stage of disease infection. The patients' bodies, clothing, and excreta all have strong infectivity, and disinfection and isolation work should be done well. Strictly disinfect the patients' excreta according to the isolation principles of enteric infectious diseases until the isolation period is lifted. At the same time, prevention and treatment of recurrence and relapse of typhoid should be carried out.

　　2. Early detection and identification of carriers, preventing chronic carriers from engaging in work they should not be engaged in, and conducting medical observation on people in close contact with typhoid patients to reduce the spread of the disease.

　　3. Improving the environment, protecting water sources, and preventing the pollution of water sources with feces containing typhoid bacilli to cause acute waterborne outbreaks. In the process of food production, processing, transportation, and sales, it is necessary to prevent the contamination of carriers or patients' excreta, and to prevent the spread of foodborne transmission. Pay attention to dietary hygiene and the disinfection of drinking water, develop good hygiene habits, and improve the level of hygiene.

　　1. Blood routine:White blood cell count increases on the basis of the original level, more than 1/3 of the patients exceed 10×109/L, and some may reach above 20×109/L (in the peritonitis stage).

　　2. Serum:Typhoid agglutination test (Widal test) O antibody titer above 1:80 and H antibody titer above 1:160 have diagnostic value.

　　3. Bacteriological culture:Discovering typhoid bacilli.

　　4. X-ray examination:More than 70% of patients can be seen with free gas in the lower abdomen.

　　1. Increase water intake:Daily requirement is 2000 to 3000 milliliters (depending on the specific situation of the child), including liquid foods and beverages.

　　2. High energy intake:High-protein, high-carbohydrate diets should choose high-quality proteins such as milk, eggs, fish, chicken, shrimp, and beef, mutton, pork, and liver. Appropriate soy products can also be added. Soy milk, tofu, tofu skin, etc., carbohydrates should account for more than 60% of total energy. Eat more congee, lotus root starch, fried noodles, egg flower soup, rice porridge, etc.

　　3. Moderate fat intake:Provide appropriate digestible fats such as butter, egg yolks, and sesame oil to increase energy intake.

　　4. High vitamin content:Such as strained tomatoes, carrots, watermelons, strawberry juice, etc. Vitamin tablets can be taken if necessary.

　　5. Try to eat non-irritating foods and adhere to small meals with frequent eating:It is necessary to strictly limit coarse fiber foods such as vegetables, hard fruits, fresh fruits, and coarse grains. They should be supplied in the form of purees and mashed vegetables. Protein foods should be prepared to be soft and easy to digest, and fried or fried foods should not be consumed. The amount of food per meal should not be too much, and it is better to eat small meals. Eat 6 to 7 meals a day or more. All raw and cold vegetables and fruits should be avoided.

　　6. Pay attention to observing and adjusting the diet in time:Reduce the intake of milk and sucrose; reduce fat intake if diarrhea occurs; if intestinal bleeding or perforation occurs, stop eating immediately. If the condition permits, start with a small spoon of warm water or diluted salt water, gradually to fruit juice water. After bleeding stops, use oil-free meat broth, fresh fruit juice, milk, etc. As the condition improves, use steamed egg custard, egg soup, etc. After one week, eat semi-liquid or soft food with less residue.

　　7. Typhoid food therapy recipe

　　Portulaca oleracea decoction:Portulaca oleracea 60 to 90 grams (double for fresh), dolichos lablab flower 10 to 12 grams, decocted with brown sugar, taken twice a day. Or portulaca oleracea burned to a residue, ground into powder, and taken with sugar, 6 grams per time, twice a day.

　　1. Treatment

　　1. Surgical treatment:Typhoid perforation is one of the serious complications of typhoid fever, which often occurs in the 2nd to 3rd week of the course. At this stage, the inflammatory reaction of the lymphatic tissue in the intestinal wall is most significant, and it is easy to induce perforation due to poor intestinal function, increased intraluminal pressure, or disturbance by ascaris.

　　Once diagnosed with typhoid perforation, active preoperative preparation should be made under the condition permitted, and timely laparotomy exploration and surgical treatment should be carried out. Due to the poor physical condition and severe condition of the patients, the operation should adopt a short-duration, simple operation, minimal interference to the body, and minimal tissue damage. The operation of perforation repair and abdominal drainage is simple and can usually meet the above requirements, and intestinal resection should not be performed lightly. If the patient's condition is extremely serious and does not meet the conditions for surgery, bedside abdominal drainage can be performed, and at the same time, a sufficient amount of effective antibiotics should be administered to control infection, strengthen parenteral nutrition support, and carry out necessary symptomatic treatment to strive for stable condition before surgery.

　　Laparotomy exploration generally adopts a lower right abdominal incision, and the exploration must be based on the principle of thoroughness. 80% of perforations occur within 50 cm of the ileocecal valve in the distal ileum, where the blood circulation of the small intestine is the worst, the intestinal wall is relatively thin, the pressure it withstands is large, and it is easy to perforate. Typhoid perforation is mostly round or elliptical, with the surrounding intestinal tract congested and swollen, covered with a fibrinous pus film, and the mesenteric lymph nodes are enlarged.

　　The problems faced by repair surgery are that the intestinal wall at the site of typhoid perforation is already congested and swollen, with fragile tissue that is easily cut by sutures. To reduce the occurrence of intestinal fistula, the entry point of the needle should be slightly away from the margin of the perforation, at least 0.5 to 1.0 cm from the edge. When performing seromuscular layer suture, the spacing between the interrupted sutures should be more than 0.5 cm, and a subcutaneous suture should be made between the seromuscular layers to prevent the intestinal wall from being torn. Pay attention to the tightness of the suture knots, neither cutting the intestinal tract nor too loose. If there is only one perforation, the tissue of the adjacent intestinal wall is basically normal, and the simple perforation repair can usually heal well. If the perforation is large, the surrounding intestinal wall is edematous and brittle, and it is estimated that it will be difficult to heal after suture, and a proximal intestinal stoma can be added after repairing the perforation. One should not be satisfied with the discovery of a single perforation, and the exploration must involve the entire intestine, paying attention to multiple perforations. For those who do not have the conditions for a single suture, ileal stoma can be selected for intestinal cavity drainage. Pericolic suture should be performed on those with impending perforation.

　　In order to improve the efficacy of surgery, in addition to reliable suture, it should be emphasized that the pus that may remain in the concave and hidden orifices in the abdominal cavity must be aspirated to reduce the residual bacteria. Place abdominal drainage to reduce bacterial infection and the absorption of toxins, and give effective antibiotics and supportive treatment to improve the body's ability to resist diseases.

　　Due to the difficulty of the intestinal typhoid patients to tolerate major surgical trauma, the principle should be to complete the operation as quickly as possible with the simplest surgical method. However, when there is uncontrollable massive hemorrhage, consideration should be given to intestinal resection and anastomosis. If the right lower quadrant oblique incision does not expose sufficiently, it can be changed to an abdominal exploration incision, part of the original incision is sutured, and the rest is used for abdominal drainage. Those who adopt a large abdominal exploration incision can perform abdominal lavage to further remove abdominal pollutants, reduce the absorption of bacteria and toxins, and cause systemic reactions. Abdominal lavage fluid can be used for normal saline, gentamicin, and metronidazole solution.

　　2. General treatment

　　(1) Isolation treatment: After surgery, continue to isolate as an intestinal infectious disease and perform fecal culture every 5-7 days. After two negative cultures, isolation is lifted.

　　(2) Nursing care: After admission, isolation and disinfection of the ward should be carried out immediately, and health education and psychological care should be provided. Strictly observe the condition and keep good records. For critically ill patients, strengthen oral care, keep the skin clean, change positions regularly to prevent bedsores, prevent pulmonary infection, and take physical cooling measures when feverish.

　　(3) Attention should be paid to the maintenance of water and electrolyte balance and acid-base balance: Timely supplementation of fluids containing sodium, potassium, calcium, and other ions, timely adjustment of acid-base imbalance in the body through blood gas testing, correction of metabolic acidosis, and improvement of oxygen supply status of the body.

　　(4) Diet: After the postoperative recovery is smooth, the bowel sound returns, and as soon as there is gas and defecation, eating can begin. Initially, a diet containing sufficient calories and protein, such as liquid or soft, non-gritty food, should be given in small and frequent meals, and then gradually transition to normal diet. Adults should be provided with about 6688KJ (1600kcal) of calories per day, along with sufficient vitamin B and vitamin C.

　　(5) The application of adrenal cortical hormones: Glucocorticoids have certain effects in rapid cooling, alleviating toxic symptoms, reducing organ damage, and lowering mortality. However, they cannot shorten the course of the disease and may even increase the incidence of complications and recurrence rates, so they should not be used routinely. In critically ill patients, they should be used with caution in conjunction with antibiotics. In principle, they can be applied in the following situations: ① Severe illness with high fever, physical cooling for 1-2 hours is ineffective; ② High fever accompanied by neurological symptoms; ③ Severe toxic symptoms, toxic myocarditis, severe liver and kidney damage, and adrenal cortical function减退; ④ Drug rash occurs when antibiotics are used. Short-term application of glucocorticoids does not increase the incidence of intestinal hemorrhage or perforation. Generally, intravenous administration is commonly used, with hydrocortisone 100-200mg/d or dexamethasone 5mg/d, which can quickly improve the toxicemia phenomenon. After the efficacy is achieved, the efficacy needs to be consolidated for 1-2 days.

　　(6) Enhancing immunity: Typhoid fever patients have a certain degree of immunosuppression, and human blood gamma globulin, thymosin, coenzyme Q10, transfer factor, interferon, and Astragalus membranaceus can be used to enhance humoral and cellular immune responses.

　　3. Antimicrobial therapy:Antimicrobial therapy must be used rationally according to local conditions. The preferred drugs for treatment include:

　　(1) Chloramphenicol (chloromycin): Since the application of chloramphenicol for treating typhoid fever in 1948, there has been a history of 50 years. It is still the most successful drug for treating typhoid fever. Chloramphenicol can reduce the mortality rate of typhoid fever, shorten the natural course of the disease, and reduce serious complications through its antibacterial action. Its缺点 is a high recurrence rate, an increase in chloramphenicol-resistant typhoid bacillus strains, a trend of decreasing efficacy, and it cannot reduce the carrier state, being ineffective for chronic carriers. The common side effects of chloramphenicol include nausea, vomiting, diarrhea, rash, stomatitis, and in a few cases, neurological symptoms. Severe drug reactions are mainly manifested as aplastic anemia and agranulocytosis. Due to the occasional occurrence of a severe toxic reaction after the first use of a high dose of the drug, with a rapid and massive death and dissolution of bacteria, leading to an increase in endotoxins and a worsening of toxic blood symptoms, a decrease in body temperature, and the occurrence of therapeutic shock, it is not recommended to use a shock dose for the first time. It should be avoided or used with caution in newborns, pregnant women, and individuals with significant liver dysfunction. Oral or intravenous administration, adults should take 2-4 doses a day, each dose of 0.5g. After the body temperature returns to normal, the dose can be halved 1-2 days later, and the total course of treatment is 14-21 days. A low dose of chloramphenicol of 1g/d can be used for 3 days after the body temperature returns to normal, followed by a 5-7 day drug-free period, then a half dose for about 1 week, with a total course of treatment of 14-21 days.

　　(2) Sulfamethoxazole/Trimethoprim (Co-trimoxazole, SMZ-TMP): Sulfamethoxazole/Trimethoprim is a bactericidal agent, easy to use, with low toxicity, minimal gastrointestinal reactions, mild disruption of intestinal flora, rapid disappearance of toxic symptoms, low recurrence rate, and rare occurrence of toxic crises. The carriage rate is low after treatment with sulfamethoxazole/trimethoprim. Adults should take 2 tablets twice a day (each containing 400mg of sulfamethoxazole and 80mg of trimethoprim), with a total course of treatment not exceeding 14 days. The side effects of sulfamethoxazole/trimethoprim include nausea, vomiting, rash, and occasionally central nervous system symptoms such as dizziness, headache, fatigue, vertigo, and paresthesia. It also affects the hematopoietic system, causing a decrease in white blood cells, a decrease in platelets, and anemia. There are occasional cases of liver and kidney damage, and it should be used with caution in individuals with sulfamethoxazole allergy, impaired liver and kidney function, and pregnant women.

　　(3) Ampicillin (Ampicillin): 4-6g/d, administered in 3-4 divided doses by intravenous infusion into 5% glucose solution, often used in combination with chloramphenicol. The use of ampicillin for treating typhoid fever began in 1962, and it is characterized by low toxicity and moderate cost, making it suitable for pregnant women, infants, individuals with low white blood cell counts, and those with impaired liver and kidney function. The efficacy of this drug is significantly lower than that of chloramphenicol, with a slow clinical response and a high failure rate of up to 30%, and a high incidence of drug eruptions.

　　(4) Amoxicillin: Amoxicillin has a similar antibacterial effect to ampicillin and may be superior to chloramphenicol in fever reduction, symptom improvement, reducing recurrence, and bone marrow hematopoiesis. After oral administration, the plasma concentration is twice as high as that of ampicillin. The general dose is 50 to 100mg per (kg·d), taken in four divided doses.

　　(5) Furazolidone (Lomotil): The recommended dose for adults is 800mg per day, and for children 10 to 15mg per (kg·d), taken in four divided doses, not to exceed 2 weeks, and vitamin B should be taken simultaneously. Common side effects include discomfort in the upper abdomen, nausea, vomiting, loss of appetite, and a few patients may experience peripheral neuritis.

　　(6) Enoxacin (Furadantin): Enoxacin is a fluoroquinolone antibiotic, the third generation of quinolone drugs, which can inhibit bacterial DNA gyrase, prevent chromosome separation, DNA replication, transcription, and other functions, ultimately destroying DNA to achieve the purpose of杀菌. This drug has strong antibacterial activity, good oral absorption, and strong bactericidal effect on Salmonella typhi, and is easily permeable into cells with high drug concentration in bile. The recommended dose for adults is 0.6g per day, taken in three divided doses, for 14 days consecutively.

　　(7) Gentamycin: Gentamycin has certain efficacy against typhoid fever, with the usual dose for adults being 160,000 to 240,000 U, and for children 4,000 to 6,000 U per (kg·d), administered by intramuscular or intravenous infusion in divided doses, with a course of 2 weeks. The main adverse effects are damage to the patient's auditory nerve and kidneys, and it is contraindicated in pregnant women and those with renal insufficiency.

　　(8) Thiamphenicol: Thiamphenicol is a synthetically produced broad-spectrum antibiotic with a structure similar to chloramphenicol, fewer side effects, and is suitable for treating typhoid fever caused by chloramphenicol-resistant strains. The recommended dose for adults is 1 to 2g per day, taken in two to three divided doses, with a course of 14 days. Up to 10% to 20% of patients may experience leukopenia.

　　For a long time, chloramphenicol has been used as the first-line drug for treating typhoid fever. After the emergence of chloramphenicol-resistant Salmonella typhi, ampicillin and sulfamethoxazole/trimethoprim are the first-line drugs for treating chloramphenicol-resistant Salmonella typhi. Subsequently, Salmonella typhi with multiple antibiotic tolerance mediated by plasmids has emerged. For the treatment of multidrug-resistant Salmonella typhi, the following drugs can be selected:

　　(9) Ciprofloxacin: A novel quinolone derivative with ideal pharmacokinetics, good cellular permeability, and broad-spectrum antibacterial activity. Its antibacterial spectrum is similar to that of Norfloxacin (Furazolidone), and the antibacterial activity of ciprofloxacin is 4 to 8 times higher than that of norfloxacin. It has no cross-resistance with penicillins, cephalosporins, and aminoglycoside antibiotics. The recommended dose for adults is 0.3g per time, once every 12 hours, taken orally, with a course of 10 to 14 days.

　　(10) Norfloxacin: Norfloxacin is one of the highly effective and low-toxic antibiotics used in the treatment of typhoid fever, with efficacy significantly exceeding Chloramphenicol, Ampicillin, and Sulfamethoxazole/Trimethoprim, and it is easy to use with few side effects, making it the first choice in areas with an outbreak of typhoid fever. Norfloxacin belongs to the new quinolone antibiotics, which kill bacteria by inhibiting the activity of DNA gyrase. Norfloxacin has a broad antibacterial spectrum, strong antibacterial activity, stronger antibacterial activity against Gram-negative bacteria, is rapidly absorbed orally, has a low protein binding rate, high blood concentration, and a half-life of 3-6 days. A single oral dose of 400mg achieves a blood peak concentration of 1.5-2.0 μg/mL, exceeding the minimum inhibitory concentration for Salmonella typhi. After oral administration, the concentration of the drug in tissues is high, especially in bile, which is suitable for the treatment of cholecystitis and for reducing carriers. Norfloxacin has no cross-resistance with antibiotics or similar drugs and can be used for resistant strains of aminoglycoside and cephalosporin antibiotics as well as for patients who are ineffective to Chloramphenicol. The toxic and side effects of Norfloxacin are mild, and may include gastrointestinal reactions, rash, leukopenia, etc. Caution should be exercised in patients with severe liver and kidney dysfunction. The method of using this drug: ① Single use of Norfloxacin 0.4g, 3 times a day, orally, and change to 0.4g, 2 times a day when the body temperature returns to normal; ② Norfloxacin combined with Fosfomycin for treatment, Norfloxacin administration method is the same as before, Fosfomycin 8-12g/d, administered intravenously in two divided doses; ③ Norfloxacin combined with Cefamandole (Cefoperazone) for treatment, Norfloxacin administration method is the same as before, Cefamandole (Cefoperazone) 3-4g/d, administered intravenously in two divided doses; ④ Norfloxacin combined with aminoglycoside antibiotics, Norfloxacin administration method is the same as before, Gentamicin 160,000-240,000 U/d, administered intramuscularly or intravenously, with a course of 12-14 days.

　　(11) Ofloxacin (Floxacin): Ofloxacin (Floxacin) is a third-generation derivative of the quinolone class, with a similar antibacterial spectrum to Norfloxacin. It is absorbed quickly after oral administration, with high and persistent blood concentrations, an average half-life of 6 hours, high clinical efficacy, few side effects, and safe and convenient use. Most cases show fever reduction within 5 days, with a clinical efficacy rate and bacterial culture conversion rate of 100%. The dose is 300mg, taken orally every 12 hours, with a course of 10-14 days.

　　(12) Fosfomycin: Fosfomycin can hinder the synthesis of bacterial cell walls, has bactericidal effects, and is often used in combination with Norfloxacin in clinical practice. Fosfomycin is a bacteriostatic agent during the bacterial reproductive period, which can enter bacteria at high concentrations to hinder the early synthesis of cell walls. Norfloxacin can antagonize bacterial DNA gyrase, block DNA replication, and exhibit rapid bactericidal effects. When used in combination with Norfloxacin, it can destroy bacteria from different parts of the bacteria, exerting a dual bactericidal effect and effectively preventing the production of L-type bacteria. Fosfomycin can enter the bone marrow, blood, liver, spleen, kidneys, and other tissues to kill residual Salmonella typhi, improve efficacy, and reduce recurrence. It can also be used in combination with Ampicillin, Amoxicillin (Hydroxymethylpenicillin), or Trimethoprim (TMP). The recommended dose for adults is 4-16g/d, administered by intravenous infusion in divided doses, and used continuously for 2 weeks.

　　(13) Rifampicin: Rifampicin is one of the first-line drugs for refractory typhoid, with bactericidal effects on a variety of Gram-positive cocci and Gram-negative bacilli, and is also effective against drug-resistant typhoid bacilli. Rifampicin is inexpensive, easy to use, and has few toxic and side effects. The dose for adults is 0.6g/d, taken on an empty stomach, and at least 3 weeks of medication should be continued after the fever subsides, with a total course of not less than 2 weeks. Regular liver function tests should be performed during use.

　　(14) Cephalosporins: The second and third generation cephalosporins have a good effect on treating drug-resistant typhoid, with high drug concentration in the biliary tract, few toxic and side effects, rapid fever reduction, and low recurrence rate. Commonly used drugs include: ① Cefamandole (cefamandole) with a dose of 4 to 8g/d, administered twice by intramuscular or intravenous injection; ② Cefoperazone, 4 to 6g/d for adults, administered four times by intramuscular or intravenous injection; ③ Ceftriaxone (cefotetan) is suitable for adult cases with high fever that does not subside after using a variety of antibacterial drugs, with a dose of 2g per dose, twice a day, and the dose is halved after the body temperature returns to normal. The above drugs are given for 10 to 14 days as one course.

　　When treating typhoid with medication, attention should be paid to: ① It is advisable to perform blood culture and drug sensitivity test to select antibiotics. ② The course of antibacterial drugs is generally 2 to 3 weeks, and it is advisable to observe the effect of a drug for 7 to 10 days, and change the drug if there is still no effect. ③ The drug concentration in the blood should be maintained continuously.

　　II. Prognosis

　　Generally speaking, the prognosis of typhoid perforation is closely related to the timing of surgical treatment and the overall condition of the patient. It is reported that the mortality rate is 10% within 24 hours after perforation; 30% between 48 to 72 hours; and up to 50% for those who have presented with shock. In the future, with the development of medicine and the improvement of diagnosis, the prognosis of this disease will be significantly improved. There are already reports that the mortality rate of surgery is below 10%.