Intestinal typhoid perforation

　　I. Etiology

　　The typhoid bacillus only resides in humans and becomes the source of infection for this disease. People get infected by consuming polluted water or food, or by direct or indirect contact with the feces of patients or carriers. Intestinal perforation is one of the serious complications of typhoid fever.

　　II. Pathogenesis

　　1. Pathogenesis:Most of the typhoid bacilli entering the digestive tract with polluted water or food are killed by gastric acid. When the number of bacteria entering the body exceeds 100,000, or when gastric acid is reduced due to certain diseases, 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 or intercellular spaces of the small intestinal mucosa, and invade the lymphoid tissue of the intestinal wall, where they are engulfed by phagocytes and multiply. Some bacteria enter the mesenteric lymph nodes through lymphatic vessels, multiply 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, and multiply there. The bacteria engulfed by phagocytes enter the blood again, 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), and others, causing acute changes in inflammatory tissues. Severe inflammatory reactions and mononuclear cell infiltration can cause necrosis, shedding, and ulceration of the intestinal mucosa. If the lesion involves blood vessels, it can cause intestinal bleeding. If the ulcer invades the muscular and serosal layers of the intestinal wall, it can cause intestinal perforation.

　　2. Pathology:The pathological changes of typhoid fever mainly occur in the terminal ileum within 100cm from the ileocecal valve, where the mesenteric lymph nodes swell due to congestion, edema, and hyperplasia. Ulcers on the intestinal wall appear with the necrosis and shedding of lymphoid nodules, and if the ulcers invade blood vessels, they 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 peristalsis becomes hyperactive. The pathological process of typhoid fever can be divided into four stages, namely, the hyperplastic stage, the necrotic stage, the ulcerative stage, and the healing stage, based on clinical manifestations and pathological characteristics.

　　(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 lymphocytes become明显swollen. After the typhoid bacillus is engulfed by monocytes-macrophages, most of them continue to multiply within the cells and spread throughout the body with 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 of the swollen intestinal wall lymphoid tissue, which then merges and expands into a patchy area.

　　(3) Ulcerative phase: the third week of the disease 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 submucosa, but some can reach the muscular layer, even involving the serosa.

　　(4) Healing phase: the fourth week of the disease course. After the ulcer is formed, new granulation tissue appears in the submucosa and is covered by the regenerating intestinal mucosal epithelium to heal.

　　In the third week of the disease course, the ulcerative phase, the small intestine is prone to perforation at the center of inflammatory infiltration of the elliptical ulcer. According to statistics, about 90% of perforations occur within 100 cm from the ileocecal valve, but there are also individual cases where perforations occur in the jejunum, appendix, cecum, and other places. Most typhoid enteritis perforations are solitary, with diameters of 0.5 to 1.0 cm, and about 10% of patients have 2 to 4 perforation sites, and some can reach more than 10. In some cases, the surrounding area of a solitary perforation may show that the ulcerative lesions have made the intestinal wall very thin, forming an impending perforation. Because typhoid enteritis rarely causes peritoneal reaction and adhesion, perforation often leads to diffuse peritonitis, which is rarely contained and localized or forms an internal fistula. There may be a lot of free fluid in the abdominal cavity, and abscesses can form in the lower right abdomen or pelvis.

　　The typhoid bacillus enters various organs of the body, such as the liver, spleen, kidneys, gallbladder, etc., and multiplies there. The bacteria that are engulfed by phagocytes enter the blood again, causing a second bacteremia, activating sensitized lymphocytes to produce 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 acute changes in inflammatory tissues. Severe inflammatory reactions and mononuclear cell infiltration can cause necrosis, desquamation, and ulceration of the intestinal mucosa. Lesions involving blood vessels can cause intestinal bleeding, and ulcers that invade the muscularis mucosae and serous layer of the intestinal wall can cause intestinal perforation.

　　Perforation of typhoid enteritis often occurs with typhoid fever, which is more common in summer and autumn. According to statistics, the incidence of perforation in typhoid enteritis is generally about 5%, with 60% to 70% of perforations occurring within the second or third week of the disease course, 10% to 20% occurring in the first week, and some occurring in the fourth week or later. Typical clinical manifestations include:

　　1Symptoms of typhoid fever:Typical intestinal typhoid fever has persistent high fever, abdominal pain, constipation or diarrhea, enlargement of the liver and spleen, relative bradycardia, and leukopenia. The typical clinical course can be divided into 5 stages, namely:

　　1, Incubation period:From 3 to 60 days, usually 8 to 14 days, the incubation period varies with the size of the infective dose and the strength of the body's immune ability. In individuals with low immune function, the incubation period is shorter. In cases of waterborne infection, the amount of bacteria ingested is less, and the incubation period is longer.

　　2, Initial stage:Corresponds to the 1st week of the course, usually with a concealed onset. The earliest symptom is fever, with a stepwise rise in body temperature, reaching 39℃ to 40℃ within 5 to 9 days. It is often accompanied by general malaise, aversion to cold, muscle ache, decreased appetite, distension, constipation, or mild diarrhea, sore throat, cough, etc.

　　3, Acute phase:Corresponds to the 2nd to 3rd week of the course, when the typical manifestations of typhoid fever often occur. During this period, about 5% of patients develop intestinal perforation and hemorrhage.

　　① High fever: It usually presents as a稽留热 pattern, with persistent high fever that does not subside, especially common in drug-resistant typhoid fever patients. A few patients present with a remittent fever pattern or irregular pattern, with fever lasting for 10 to 14 days.

　　② Relative bradycardia: In typhoid fever patients, relative bradycardia occurs when the body temperature is between 38℃ and 39℃. This is one of the representative manifestations of typhoid fever patients. Healthy people have a corresponding increase in pulse rate as the body temperature rises, generally estimated by a simple method: for every 1℃ increase in body temperature, the pulse rate increases by 10 beats per minute.

　　4, Remission period:Corresponds to the 4th week of the course, with body temperature gradually decreasing from the end of the 3rd week to normal by the end of the 4th week. The condition begins to improve, with a remittent fever pattern of body temperature, which gradually decreases, and various symptoms gradually subside, with an improvement in appetite.

　　5, Recovery period:Around the 5th week of the course, the patient enters the recovery phase, with clinical symptoms improving before the pathological recovery. The patient's body temperature returns to normal, symptoms gradually subside or disappear, appetite increases significantly, and there is a feeling of hunger. There may be excessive sweating. In addition to the above typical onset form, some patients have atypical presentations, some presenting with pneumonia, showing sepsis symptoms on the 1st to 2nd day of onset, with symptoms and signs of lobar pneumonia, and typhoid bacilli may be found in sputum. Some patients present with arthritis, similar to the early stages of rheumatic fever, and some may present with pleurisy, typhoid nephritis, cholecystitis, or severe jaundice.

　　Symptoms of intestinal typhoid perforation:Perforation of the intestine is the most serious complication of typhoid fever, often occurring in the 2nd to 3rd week after the onset of symptoms, more commonly in patients with severe abdominal pain, distension, and tenderness. Some cases occur several days after treatment, when the patient has already begun to improve and suddenly develops perforation. After perforation, the patient reports pain in the lower right abdomen, accompanied by nausea, vomiting, rapid and weak pulse, cold sweat, and temporary drop in body temperature (shock phase). After 1 to 2 hours, abdominal pain and other symptoms may slightly subside (quiet phase), and soon, the patient develops persistent abdominal pain, a painful expression, and a rapid rise in body temperature. Physical examination reveals peritonitis symptoms throughout the abdomen, with the lower right abdomen being particularly pronounced, with generalized abdominal tenderness, rebound tenderness, muscle tension, and reduced or disappeared liver dullness.

　　1. When typhoid patients receive surgical treatment, they are exactly in the peak stage of disease infection. The body, clothing, and excrement of the patients all have strong infectivity, and disinfection and isolation work should be done well. According to the isolation principles of intestinal infectious diseases, the excrement of the patients should be thoroughly disinfected until the isolation period is lifted. At the same time, prevent and treat the recurrence and relapse of typhoid fever.

　　2. Discover and detect carriers in a timely manner, prevent chronic carriers from engaging in work they should not do, and carry out medical observation for people in close contact with typhoid fever patients to reduce the spread of the disease.

　　3. Improve the environment, protect water sources, prevent feces containing typhoid bacilli from contaminating water sources to cause acute waterborne outbreaks. During the production, processing, transportation, and sales of food, it is necessary to prevent the contamination of carriers or patients' excrement, causing foodborne transmission. Pay attention to dietary hygiene and water disinfection, develop good hygiene habits, and improve the level of hygiene.

　　4. Vaccination with typhoid vaccine can reduce the incidence rate. It is necessary to continue vaccination and reinforcement every year to make susceptible populations active immunization objects.

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

　　2. Serological typhoid agglutination test (Widal test): The titer of O antibody is above 1:80, and the titer of H antibody is above 1:160, which has diagnostic value.

　　3. Bacteriological culture: typhoid bacilli are found.

　　4. X-ray examination: More than 70% of patients show free gas under the diaphragm.

　　5. Diagnostic abdominal puncture can assist in diagnosis.

　　What kind of food is good for typhoid enteritis perforation

　　Postoperative recovery is smooth, bowel sounds return, and when 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 provide about 6688KJ (1600kcal) of calories per day, and at the same time, sufficient vitamin B and vitamin C should be provided.

　　1. Treatment

　　1. Surgical Treatment

　　Perforation of typhoid fever 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 of the intestinal wall is most significant. Once the intestinal function is poor, the intraluminal pressure increases, or ascaris disturbs, perforation is easily induced.

　　Perforation of typhoid enteritis should be actively prepared for preoperative care as soon as diagnosed, and timely laparotomy and surgical treatment should be performed. Due to the poor physical condition and severe condition of the patient, 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 often meet the above requirements, and it should not be easily performed for intestinal resection. If the patient's condition is extremely severe and does not meet the surgical conditions, 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, perform necessary symptomatic treatment, and strive for stable condition before surgery.

　　Laparotomy exploration usually uses a right lower abdominal incision, and the exploration must be thorough. 80% of perforations are within 50 cm of the ileocecal valve in the distal ileum, which has the worst blood circulation among the small intestines, a relatively thin intestinal wall, and greater pressure, making it more prone to perforation. Perforations in typhoid fever are mostly round or elliptical, with surrounding intestinal swelling, covered with纤维素 pus, and enlarged mesenteric lymph nodes.

　　The problem faced by the repair surgery is that the intestinal wall at the typhoid perforation site is already congested and swollen, with fragile tissue, which is easily cut by the suture thread. To reduce the incidence of intestinal fistula, the needle entry point should be slightly away from the perforation margin during full-thickness invagination suture, at least 0.5 to 1.0 cm from the edge. When performing serosal muscle layer suture, the spacing between the intermittent sutures should be more than 0.5 cm, and the needle should first have a subcutaneous course between the serosal muscle layers to prevent the intestinal wall from being torn. Pay attention to the tightness of the suture knot, neither cutting the intestinal tract nor too loose. If there is only one perforation, the surrounding intestinal wall tissue is basically normal, and the simple perforation repair can usually heal well. If the perforation is large, the surrounding intestinal wall is edematous and fragile, and it is estimated that it will be difficult to heal after suture, so additional proximal intestinal fistula surgery can be used after repairing the perforation. Do not be satisfied with the discovery of a single perforation, the exploration must involve the entire intestinal tract, and attention should be paid to multiple perforations. For those who do not have the conditions for one-time suture, ileal proximal fistula surgery can be chosen for intestinal lumen drainage. Peritoneal muscle layer suture should be performed for those with urgent perforation.

　　To improve the efficacy of surgery, in addition to reliable suture, it must be emphasized that the pus in the intraperitoneal concave and recess areas must be aspirated to reduce the residual bacteria. Place abdominal drainage to reduce bacterial infection and toxin absorption, and provide effective antibiotics and supportive treatment to enhance the body's resistance to disease.

　　Due to the difficulty of intestinal typhoid patients tolerating large 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 bleeding, consideration should be given to intestinal resection and anastomosis. If the right lower abdominal oblique incision does not expose sufficiently, it can be changed to an abdominal exploration incision, with part of the original incision sutured and the rest used for abdominal drainage. For those who have large abdominal exploration incisions, abdominal lavage can be performed to further remove intraperitoneal contaminants, reduce the absorption of bacteria and toxins, and cause systemic reactions. Abdominal lavage fluid can be used with normal saline, gentamicin, and metronidazole solution.

　　2. General treatment

　　(1) Isolation and treatment: After surgery, isolation should continue to be carried out according to intestinal infectious diseases, and fecal culture should be performed every 5 to 7 days. Isolation is lifted after two negative cultures.

　　(2) Nursing care: Upon admission, isolation and disinfection of the ward should be carried out immediately, and education and psychological care should be provided. Strictly observe the condition and keep good records. For severely ill patients, strengthen oral care, keep the skin clean, change positions regularly to prevent bedsores, prevent pulmonary infection, and take physical降温 measures during high fever.

　　(3) Pay attention to the maintenance of water, electrolytes, and acid-base balance: timely supplement liquids containing sodium, potassium, calcium, and other ions. Adjust the body's acid-base imbalance in a timely manner through blood gas testing to correct metabolic acidosis and improve the body's oxygen supply status.

　　(4) Diet: After the postoperative recovery is smooth, the bowel sound returns, and the patient can have排气 and defecation, they can start to eat. Initially, a diet containing sufficient calories and protein, such as a liquid or soft, non-grainy diet, should be provided in small quantities and multiple meals. Gradually transition to normal diet. Adults should be supplied with about 6688KJ (1600kcal) of calories per day, and sufficient vitamin B and vitamin C should also be provided.

　　(5) Application of adrenal cortex hormones: Corticosteroids have certain effects on rapid cooling, alleviating poisoning 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, so they should not be used routinely. They should be used with caution in critically ill patients in conjunction with antibiotics. In principle, they can be applied to:

　　① Severe condition, with high fever, physical cooling for 1-2 hours is ineffective;

　　② High fever accompanied by neurological symptoms;

　　③ Severe poisoning symptoms, myocarditis, severe liver and kidney damage, and adrenal cortex function insufficiency;

　　④ Drug eruption when applying antibiotics. Short-term use of corticosteroids does not increase the incidence of intestinal hemorrhage or perforation. Generally, it is given intravenously, with hydrocortisone 100-200mg/day or dexamethasone 5mg/day, and the symptoms of toxicemia will improve quickly after administration. After the efficacy appears, it is necessary to consolidate the efficacy for 1-2 days.

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

　　3. Pathogen treatment:

　　The treatment of the pathogen must be based on the local conditions and use antibiotics rationally. The preferred drugs for treatment include:

　　(1) Chloromycin: Since the application of chloromycin for the treatment of typhoid fever in 1948, it has a history of 50 years and is still the most successful drug for the treatment of typhoid fever. Chloromycin can reduce the mortality rate of typhoid fever, shorten the natural course of the disease, and reduce serious complications through its antibacterial action. Its disadvantages include a high recurrence rate, an increase in chloromycin-resistant typhoid bacillus strains, a tendency for efficacy to decrease gradually, and it cannot reduce the carrier state or be effective for chronic carriers. The common side effects of chloromycin include nausea, vomiting, diarrhea, rash, and stomatitis, with a few cases showing 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 application of a large dose of the drug, with rapid and massive death and dissolution of bacteria in a short period of time, a large amount of endotoxin is released, causing the symptoms of toxicemia to worsen, the body temperature to drop, and treatment shock to occur, 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 those with significant liver function damage. Oral or intravenous injection, adults 2-4 times a day, 0.5g each time, the dose can be halved 1-2 days after the body temperature returns to normal, a course of 14-21 days. A low-dose chloromycin treatment of 1g/day, after the body temperature returns to normal, it should be used for 3 more days, stop the medicine for 5-7 days, and then use half the dose for about a week, with a total course of 14-21 days.

　　(2) Sulfamethoxazole/Trimethoprim (Co-trimoxazole, SMZ-TMP): Sulfamethoxazole/trimethoprim is a bactericidal agent that is easy to use, has low toxicity, minor gastrointestinal reactions, mild disruption of intestinal flora, rapid disappearance of toxic symptoms, low recurrence rate, and rarely causes toxic crises. The rate of carriage after treatment with sulfamethoxazole/trimethoprim is low. The recommended dose for adults is twice a day, each time two tablets (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 sensory abnormalities. It also affects the hematopoietic system, causing a decrease in white blood cells, a decrease in platelets, and anemia. There is also occasional damage to liver and kidney function, and caution should be exercised in patients with sulfamethazole allergy, impaired liver and kidney function, and pregnant women.

　　(3) Ampicillin (Ampicillin): 4-6g/d, administered in three to four divided doses by intravenous infusion into a 5% glucose solution, often used in combination with chloramphenicol. The use of ampicillin in the treatment of typhoid fever began in 1962. It has low toxicity, moderate cost, and can be used in pregnant women, infants, patients with low white blood cell count, and those with impaired liver and kidney function. The efficacy of this drug is much lower than that of chloramphenicol, with a slow clinical effective response and a failure rate as high as 30%, and a high incidence of drug rash.

　　(4) Amoxicillin: The antibacterial action of amoxicillin is similar to that of ampicillin, and it may be superior to chloramphenicol in reducing fever, improving symptoms, reducing recurrence, and in bone marrow hematopoiesis. The plasma concentration after oral administration is twice that of ampicillin. The usual dose is 50-100mg/(kg·d), taken in four divided doses orally.

　　(5) Furazolidone (Tetramidine): Adults take 800mg/d, children 10-15mg/(kg·d), taken in four divided doses, not to exceed 2 weeks, and Vitamin B should be taken concurrently. Common side effects include discomfort in the upper abdomen, nausea, vomiting, loss of appetite, and a few patients may develop peripheral neuritis.

　　(6) Enoxacin (Floxacin): A fluoroquinolone antibiotic, it is a third-generation quinolone drug that can inhibit bacterial DNA gyrase, prevent chromosomal separation, DNA replication, transcription, and other functions, ultimately destroying DNA to achieve the purpose of杀菌. The antibacterial activity of this drug is strong, with good oral absorption, and it has a strong bactericidal effect on Salmonella typhi. It is also easy to penetrate into cells and has a high concentration of the drug in bile. The recommended dose for adults is 0.6g/d, taken in three divided doses, for a continuous period of 14 days.

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

　　(8) Thiamphnicol: Thiamphnicol is a synthetic broad-spectrum antibiotic with a structure similar to chloramphenicol, with fewer side effects and suitable for the treatment of typhoid fever caused by resistant chloramphenicol strains. The recommended dose for adults is 1 to 2g per day, taken in 2 to 3 divided doses, for a course of 14 days. 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 Salmonella typhi resistant to chloramphenicol, ampicillin and sulfamethoxazole/trimethoprim have become the first-line drugs for treating Salmonella typhi resistant to chloramphenicol. Subsequently, Salmonella typhi resistant to multiple antibiotics mediated by plasmids has emerged. For the treatment of multi-drug resistant Salmonella typhi, the following drugs can be selected:

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

　　(10) Norfloxacin: Norfloxacin is one of the effective and low-toxic antibiotics currently used to treat typhoid fever, with its efficacy significantly exceeding chloramphenicol, ampicillin, and sulfamethoxazole/trimethoprim. It is easy to use with few side effects and can be used as 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. It has a broad spectrum of antibacterial activity, strong antibacterial action, and stronger antibacterial activity against Gram-negative bacteria. It is absorbed quickly by oral administration, with a low serum protein binding rate, high blood concentration, and a half-life of 3 to 6 days. A single oral dose of 400mg results in a blood peak concentration of 1.5l/L, exceeding the minimum inhibitory concentration for Salmonella typhi. The concentration of the drug in tissues is high after oral administration, especially in bile, which is suitable for the treatment of concomitant cholecystitis and to reduce carriers. Norfloxacin has no cross-resistance with antibiotics or similar drugs and can be used for strains resistant to aminoglycosides 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, and leukopenia. Caution should be exercised in patients with severe liver and kidney dysfunction. The method of using this drug is:

　　① Single use of norfloxacin 0.4g, 3 times/d, taken orally; when the body temperature returns to normal, change to 0.4g, 2 times/d;

　　② Combination of norfloxacin with fosfomycin for treatment: The administration method of norfloxacin is the same as before, fosfomycin 8-12g/d, administered by intravenous infusion in two divided doses;

　　③ Combination of norfloxacin with cefmenoxime (cefhydroxime) for treatment: The administration method of norfloxacin is the same as before, cefmenoxime (cefhydroxime) 3-4g/d, administered by intravenous infusion in two divided doses;

　　④ Combination of norfloxacin with aminoglycoside antibiotics: The administration method of norfloxacin is the same as before, gentamicin 160,000-240,000 U/d, administered by intramuscular or intravenous infusion, for 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 rapidly absorbed after oral administration, with high and sustained blood concentrations, an average half-life of 6 hours, high clinical efficacy, few side effects, and safe and convenient use. Most cases have a 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, for a course of 10-14 days.

　　(12) Fosfomycin: Fosfomycin can inhibit 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 growth phase, which can enter the bacterial body at high concentrations to inhibit the early synthesis of the cell wall. 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 remaining typhoid bacilli, improve efficacy, and reduce recurrence. It can also be used in combination with ampicillin, amoxicillin (hydroxymethylpenicillin), or methoxazole (TMP). The usual dose for adults is 4-16g/d, administered by intravenous infusion in divided doses, for a continuous period of 2 weeks.

　　(13) Rifampicin: Rifampicin is one of the first-line drugs for refractory typhoid. It has 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 is required after the fever subsides, with a total course of not less than 2 weeks. Liver function should be checked regularly during use.

　　(14) Cephalosporins: The efficacy of second and third-generation cephalosporins in treating drug-resistant typhoid is good. They have high drug concentrations in the biliary tract, few toxic and side effects, rapid fever reduction, and low recurrence rate. Commonly used drugs include:

　　① Cefamandole, 4 to 8g/d, administered intramuscularly or intravenously in two divided doses;

　　② Cefoperazone, 4 to 6g/d for adults, administered intramuscularly or intravenously in four divided doses;

　　③ Ceftriaxone (cefmetazole) is suitable for adult cases with ineffective response to multiple antibacterial drugs and persistent fever, with a dose of 2g per time, 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 tests 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. If there is still no effect, change the drug.

　　③ The drug concentration in the blood must be maintained continuously.

　　II. Prognosis

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