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Back to Journal »Drug Design, Development and Treatment» Volume 15

Clinical effect of doxycycline combined with compound sulfamethoxazole and rifampicin in the treatment of brucellosis spondylitis

Authors: Yang Xiaoming, Jia Yuling, Zhang Yu, Zhang PN, Yao Yu, Yin Yuling, Tian Yu

Published on November 23, 2021, the 2021 volume: 15 pages 4733-4740

DOI https://doi.org/10.2147/DDDT.S341242

Single anonymous peer review

Editor approved for publication: Dr. Deng Tuo

Yang Xinming, Jia Yongli, Zhang Ying, Zhang Peinan, Yao Yao, Yin Yanlin, Ye Tian, ​​Department of Orthopedics, First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, Hebei China Mailing Address: 075000 Hebei North University, No. 12, Changqing Road, Qiaoxi District, Zhangjiakou City, Hebei Province Yang Xinming Department of Orthopedics, First Affiliated Hospital Tel: +86 313-8046926 Email [email protected] Purpose: The purpose of this study is to determine the efficacy of triple antibiotics of doxycycline, compound sulfamethoxazole and rifampin in the treatment of brucellosis spondylitis Clinical Value. Methods: A retrospective analysis of 100 patients with brucellosis spondylitis admitted to the First Affiliated Hospital of Hebei North University from March 2016 to June 2019, and the patients were divided into the following two groups: control group (n=50 ) Antibiotic therapy (rifampicin + compound sulfamethoxazole), the observation group (n=50) was given triple antibiotic therapy (rifampicin + doxycycline + compound sulfamethoxazole). The treatment effect, relief of low back pain, erythrocyte sedimentation rate (ESR), procalcitonin (PCT), C-reactive protein (CRP) levels and the occurrence of adverse reactions were compared between the two groups. Results: The effective rate of the observation group was significantly higher than that of the control group (P <0.05). Before treatment, there was no significant difference in the levels of visual analog scale (VAS), ESR, PCT, and CRP between the two groups (P>0.05). However, the VAS score and ESR, PCT and CRP levels of the observation group after treatment were lower than those of the control group (P <0.05). There was no significant difference in the incidence of adverse reactions (P> 0.05). Conclusion: The triple antibiotics of doxycycline, compound sulfamethoxazole and rifampicin are effective in the treatment of brucellosis spondylitis. It can significantly reduce the patient's back pain and inflammation, and has high safety, which is worthy of clinical application. [Keywords]: doxycycline compound sulfamethoxazole rifampin Brucella spondylitis

Brucellosis spondylitis, referred to as brucellosis, is a zoonotic disease caused by brucellosis infection. When Brucella infection invades the human body, it spreads through the blood to all organs of the body. When it invades the spine, it is clinically called brucellosis spondylitis, or brucellosis spondylitis. 1-3 In the late 1970s and 1980s, the prevalence of the disease tended to ease. However, with the development of animal husbandry in recent years, patients with brucellosis have gradually increased, with an incidence rate of 2% to 53%. 4-6 Inflammation caused by brucellosis often involves the spinal cord and nerve roots. In severe cases, it can lead to neurological symptoms and even paraplegia. 5,7 At present, antibiotics are an important treatment for this disease, and double or even triple antibiotics are often used in clinical treatment. Therefore, the selection of antibiotics in clinical practice should be more cautious. 8,9 This study retrospectively analyzed the clinical data and treatment status of 100 patients admitted to our hospital from March 2016 to June 2019. The report is as follows.

A retrospective analysis of 100 patients with brucellosis spondylitis admitted to the First Affiliated Hospital of Hebei North University from March 2016 to June 2019 will receive dual antibiotic therapy (rifampicin + compound sulfamethoxazole) Of patients were included in the control group (n=50), and patients who received triple antibiotic therapy (rifampicin+doxycycline+compound sulfamethoxazole) were assigned to the observation group (n=50). Inclusion criteria: (1) All patients had a history of exposure to cattle and sheep in varying degrees, or a history of eating uncooked beef and mutton or drinking non-pasteurized dairy products. (2) All patients had slow onset, accompanied by flaccid hypothermia (body temperature <38.5℃), night sweats, and fatigue; (3) Diagnosis of brucellosis spondylitis based on medical history and imaging; (4) Did not reach surgery Indications for treatment. Exclusion criteria: (1) Those who are younger than 18 years old or older than 70 years, or are pregnant or breastfeeding; (2) Those who are allergic to study drugs; (3) Those who have serious heart, brain, liver, kidney or hematopoietic system, etc. Primary disease; (4) Patients with mental illness; (5) People who cannot take medication on time or terminate treatment on their own as required; (6) People with incomplete medical records. The general data of the two groups are comparable, and there is no significant difference in gender, age, course of disease, lesion location, bacterial classification, etc. (P> 0.05), as shown in Table 1. This study was conducted in accordance with the revised declaration and was approved by the Ethics Committee of the First Affiliated Hospital of Hebei North University. All subjects signed an informed consent form. Table 1 Comparison of general information between the two groups

Table 1 Comparison of general information between the two groups

The result of the Brucella agglutination test was positive, and the erythrocyte sedimentation rate (ESR) increased to 32-93 mm/h. The blood routine results were within the reference range, C-reactive protein (CRP) was 28-65 mg/L, and procalcitonin (PCT) was 2.43-4.65 μg/L.

GE Lightspeed Ultra multi-slice CT scanner is used for routine scanning; GE portable C-arm X-ray machine is used for fluoroscopy; GE Signa HD high-field magnetic resonance imaging (MRI) is used for scanning T1-weighted images (T1WI) and T2-weighted images ( T2WI), short TI inversion recovery (STIR) conventional spin echo (SE) sequence, and as horizontal T1WI and T2WI. X-rays showed varying degrees of narrowing of the intervertebral disc space. The vertebrae are moth-eaten, with hyperosteogeny at the edges, and partial bone bridges. CT showed multiple small lesions in the vertebral body, mostly located on the edge of the vertebral body, with bone sclerosis on the edge of the lesion. MRI showed low signal on T1WI, high signal on T2WI, uneven signal intensity of intervertebral disc invasion, and intervertebral space stenosis. Abscesses can be seen on both sides of the vertebral body, with unclear borders. The scanned image is shown in Figure 1. Figure 1 The imaging findings of a typical case of brucellosis spondylitis. Anterior and posterior X-rays: visible vertebral bone hyperplasia, sclerosis, irregular worm-like injury, narrowing of the intervertebral space, ossification of the longitudinal ligaments of the spine, narrowing and blurring of the facet joint space (A); CT: visible bone destruction , It is mostly round, quasi-circular or patchy low-density foci with obvious hyperplastic sclerosis zone around (B); MRI: abnormal signal of vertebral bone and surrounding soft tissues can be seen, intervertebral space is narrow, and vertebral body is uneven Signal. T1WI shows low signal, while T2WI shows high signal (C).

Figure 1 The imaging findings of a typical case of brucellosis spondylitis. Anterior and posterior X-rays: visible vertebral bone hyperplasia, sclerosis, irregular worm-like injury, narrowing of the intervertebral space, ossification of the longitudinal ligaments of the spine, narrowing and blurring of the facet joint space (A); CT: visible bone destruction , It is mostly round, quasi-circular or patchy low-density foci with obvious hyperplastic sclerosis zone around (B); MRI: abnormal signal of vertebral bone and surrounding soft tissues can be seen, intervertebral space is narrow, and vertebral body is uneven Signal. T1WI shows low signal, while T2WI shows high signal (C).

Patients in both groups received routine care and were instructed to drink plenty of water and take vitamin B/C and nutrients. Patients with fever are given physical cooling or antipyretic drugs. For those in pain, they were given analgesics and told to rest. All patients were treated with a combination regimen. The control group (n=50) patients were treated with rifampicin (manufacturer: Shenyang Shuangding Pharmaceutical Co., Ltd.; SFDA approval number: H20050725; specification: 5mL: 0.3g (rifampicin)*5) and compound preparations Dual antibiotic treatment of sulfamethoxazole (manufacturer: Shan Dongfang Ming Pharmaceutical Group Co., Ltd.; SFDA approval number: H37023306; specification: 2mL: 0.4g*10 injections). Administration: Rifampicin: 0.45 g/time, qd, intravenous drip; compound sulfamethoxazole: 0.1 g/time, qd, intravenous drip. The observation group (n=50) was treated with a triple antibiotic of rifampicin, doxycycline, and compound sulfamethoxazole. Administration method: doxycycline (manufacturer: Hainan Tongkangli Pharmaceutical Co., Ltd.; SFDA approval number: H20060405; specification: 0.1g injection): 0.1g/time, qd, intravenous drip; rifampicin and compound sulfonamide The usage of metoxazole is the same as above. After the Brucella agglutination test is negative, continue to take the medicine for 2 weeks for a total of 1 to 2 courses. Both groups were prescribed a 7-day treatment period. If the Brucella agglutination test is negative after 2 treatment periods, continue medication for 2 weeks. During the treatment process, patients with high fever were given physical cooling, antipyretic and analgesic drugs, and patients with low back pain were given non-steroidal anti-inflammatory drugs. At the same time, the liver and kidney functions were tested, and liver protection treatment was given if necessary. In addition, patients are also required to stay in bed to strengthen nutritional support.

(1) Curative effect: cure: follow up for more than 6 months, the patient's clinical symptoms and signs disappeared, no fever, erythrocyte sedimentation rate, PCT, CRP levels are normal, spinal function is restored, and bone X-rays show healing. Improvement: no fever, clinical symptoms and signs have been significantly improved; ESR, PCT, CRP levels are close to normal, and spinal function has been significantly restored; X-ray films show that the bones are basically healed. Invalid: fever still exists, clinical symptoms and signs are not significantly improved; ESR, PCT, CRP levels are elevated, and spinal function is not significantly restored; X-ray shows bone healing failure, Brucella agglutination test is positive or only short-term symptom improvement. Effective rate = (cured + improved) cases/total number of cases × 100%.

(2) The visual analog scale (VAS) was used to assess the relief of patients' low back pain. The higher the score, the more severe the pain. 10

(3) Record and compare the levels of serum inflammatory indexes (ESR, PCT, CRP) before and after treatment in the two groups. PCT is measured by immunofluorescence method, and ESR and CRP are measured by automatic biochemical analyzer.

(4) The incidence of adverse reactions: gastrointestinal reactions (nausea and vomiting, abdominal pain, diarrhea), skin rash, liver and kidney damage and other adverse reactions occurred in both groups.

SPSS 22.0 statistical software and GraphPad Prism 8.0 software were used for data statistical analysis and image drawing respectively. P <0.05 is considered statistically significant. The count data is expressed as the number of cases/percentage [n (%)] and is compared by the chi-square test between groups. The measurement data is expressed as the mean±standard deviation (mean±SD); the independent sample t test is used for the comparison of the measurement data between the groups, and the paired t test is used for the comparison between the groups before and after treatment.

There were no significant differences between the two groups in terms of age, gender, course of disease, body mass index (BMI) or lesion location (P>0.05), see Table 1.

In the observation group, 15 cases were cured, 27 cases improved, 8 cases were ineffective, and the effective rate was 84%; while the control group was cured, improved, and ineffective in 10, 23, and 17 cases, respectively, with an effective rate of 66%; the observation group had a higher effective rate than the control group (P <0.05), see Table 2. Table 2 Comparison of efficacy between the two groups (n, %)

Table 2 Comparison of efficacy between the two groups (n,%)

Before treatment, there was no statistically significant difference in VAS scores between the two groups (P>0.05). After treatment, the VAS score of the observation group was significantly lower than that of the control group (P <0.05), as shown in Figure 2. Figure 2 VAS scores before and after treatment in the two groups. Note: *P <0.05.

Figure 2 VAS scores before and after treatment in the two groups.

Note: *P <0.05.

The levels of serum PCT, CRP, and ESR before treatment in the two groups were similar. However, serum PCT, CRP, and ESR levels in the observation group were significantly lower than those in the control group after treatment (P <0.05), as shown in Figure 3. Figure 3 Comparison of serum inflammation indexes between the two groups. The serum PCT (A), CRP (B) and ESR (C) levels were compared between the two groups of patients before and after treatment. Note: *P <0.05.

Figure 3 Comparison of serum inflammation indexes between the two groups. The serum PCT (A), CRP (B) and ESR (C) levels were compared between the two groups of patients before and after treatment.

Note: *P <0.05.

In the control group, there were 5 cases of gastrointestinal reactions, 3 cases of rash, 3 cases of liver damage, and 2 cases of renal damage. The total adverse reaction rate was 26%. In the observation group, 3 cases, 2 cases, 2 cases, and 2 cases of gastrointestinal reactions, rash, liver damage, and kidney damage occurred in the observation group, and the overall adverse reaction rate was 18%. There was no difference in the incidence of adverse reactions between the two groups (P <0.05), see Table 3. Table 3 The incidence of adverse reactions in the two groups of patients (n, %)

Table 3 The occurrence of adverse reactions in the two groups of patients (n, %)

Brucellosis is found worldwide. In China, the disease mainly occurs in areas with large pastoral areas such as Inner Mongolia and Xinjiang, and it is also spread sporadically in other provinces11. Brucella is a spherical gram-negative bacteria with 6 genera, including Brucella. Bovis, Br. melitensis and Br. Pigs, the first two of which are the most common species in China. 12,13 Humans are infected with Brucella without gender preference. It is caused by human contact with infected animals, eating infected food, or breathing air contaminated by Brucella. It is mainly transmitted to the human body through animals, and it is difficult to spread from person to person. Its pathogenesis is complicated, mainly related to bacteria and toxins. 14 The main clinical symptoms of the disease in the acute phase are fever, sweating, and joint pain. 15 Improper treatment can lead to the development of acute brucellosis into a chronic disease, concurrently caused by osteoarthritis, neurogenic brucellosis, etc., which seriously affects the quality of life of patients. 16 In general, after diagnosis and standardized treatment, the patient has a good prognosis and a low recurrence rate. Therefore, the choice of antibiotics, the course of treatment, and patient compliance are critical to the treatment and prognosis of the disease.

Brucellosis spondylitis is a special infectious disease. As the cones are infected with Brucella, the clinical symptoms of patients mainly include vertebral abscess, vertebral destruction, and intervertebral disc inflammation. Long-term damage will cause spinal cord damage, leading to spinal and even spinal cord lesions. 17 The "Guidelines for the Diagnosis and Treatment of Mycological Diseases" issued by the National Health Commission recommends doxycycline combined with rifampicin or streptomycin as the first-line drug for brucellosis; second-line drug treatment, that is, doxycycline combined with sulfa drugs or Tobramycin or rifampicin combined with fluoroquinolone drugs can be used as appropriate when the first-line drugs cannot be combined or are ineffective. 18,19 Brucellosis spondylitis characterized by changes is one of the complications of brucellosis in intervertebral discitis, with an incidence rate as high as 60%. 20,21 In the early stage of the disease, conservative medication is the mainstay of treatment. When conservative treatment cannot relieve pain, patients who meet the indications for surgery can choose surgery 22-24.

At present, brucellosis is mainly treated with antibiotics, including rifampicin, levofloxacin, doxycycline, streptomycin and so on. 25, 26 Clinically, antibacterial drugs that can enter cells are usually used in combination with other antibiotics to achieve the penetration of drugs into macrophages, thereby improving 27 Rifampicin and doxycycline are antibiotics that can enter cells. Rifampicin is a semi-synthetic broad-spectrum antibiotic of rifamycin, which has certain antibacterial activity against gram-negative bacteria and other pathogenic microorganisms. Its mechanism of action is to inhibit the synthesis of RNA by bacteria and block transcription, thereby blocking the synthesis of protein and DNA and exerting its antibacterial effect; but the single-agent effect is not ideal. 28,29 Doxycycline is also an antibiotic with a broad antibacterial spectrum. It has strong antibacterial activity against sensitive gram-positive cocci and gram-negative bacilli. It can quickly bind to 30 S ribosomal subunits and inhibit t-RNA binding to play an antibacterial effect. 30,31 Sulfonamides are broad-spectrum antibacterial drugs, which are mainly used clinically for the prevention and treatment of infectious diseases. In addition to their stability, they are also widely used as feed additives in veterinary clinics and animal husbandry or as therapeutic drugs for animal diseases. Sulfa antibiotics compete with sulfa drugs and dihydrofolate synthase receptors to affect the synthesis of dihydrofolate and inhibit the growth and reproduction of bacteria. 32,33 The results of this study show that the response rate of triple antibiotic therapy consisting of doxycycline, compound sulfamethoxazole and rifampicin is 84% ​​in the treatment of brucellosis spondylitis, while compound sulfamethoxazole is 84% The combined treatment rate of oxazole and rifampicin was 66%, indicating that the efficacy of triple antibiotic therapy is better than dual therapy. In addition, it was found that there were no significant differences in the VAS scores and serum PCT, CRP, and ESR levels between the two groups before treatment. However, the above indicators in the observation group after treatment were lower than those in the control group, indicating that the efficacy of triple antibiotic therapy (doxycycline + compound sulfamethoxazole + rifampin) is better than dual antibiotic therapy (compound sulfamethoxazole + rifampin) ). Relieve pain and reduce inflammation. During monotherapy, some patients may experience gastrointestinal reactions such as nausea and vomiting, as well as adverse reactions such as liver and kidney damage, especially when antibiotics are used. 34 Therefore, in the case of combined use of antibiotics, it is necessary to pay attention to and minimize the occurrence of adverse reactions. The results of this study showed that the total incidence of adverse reactions was 18% in the observation group and 26% in the control group. There was no significant difference between the two groups. It is suggested that mastering the time and dosage of doxycycline can help control and reduce the adverse reactions of combined antibiotics.

Due to the design of this study, it still has some limitations. The sample size may be too small to detect the difference between the two groups. Therefore, it is obvious from our research that the similarity of clinical results may be a type II error. Therefore, a well-designed trial with prospective data collection and sample size calculation is needed to confirm the results of this study and prove the clinical efficacy of doxycycline combined with compound sulfamethoxazole and rifampicin in the treatment of brucellosis spondylitis Effect.

In summary, compared with the dual antibiotic therapy of compound sulfamethoxazole and rifampin, the triple antibiotic of doxycycline, compound sulfamethoxazole and rifampin is more effective in the treatment of brucellosis spondylitis. It has a more significant effect on reducing pain and inflammation in patients, with higher safety, and it is worthy of clinical application.

I would like to express my gratitude to all those who helped me in the process of writing the paper. I thank my colleagues Zhang Ying and Jia Yongli for their help. They provided me with suggestions in academic research.

The authors report no conflicts of interest in this work.

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