Doxycycline Plus Trimethoprim-Sulfamethoxazole versus Doxycycline plus Rifampicin in Treatment of Brucellosis

A Randomized Controlled Trial

Abstract

Background and aim 

Brucellosis is one of the most common endemic zoonotic diseases that have large animal and human burden. Many regimens of drug combinations are used for a variable period (at least 6 weeks). Rifampicin with doxycycline is one of the most used combinations. In this respect, we aimed to compare between the efficacy of two different combinations: trimethoprim-sulfamethoxazole combined with doxycycline (TMX-Doxy) versus rifampicin combined with doxycycline (Rif-Doxy).

Patient and methods 

Between June 2020 and January 2022, 100 patients with brucellosis were included. Half of them (50 patients) received TMX-Doxy, whereas the other half (50 patients) received Rif-Doxy for 6 weeks. Follow-up was done during the treatment course and 6 months after the end of treatment to detect successfully treated cases, failed-to-treat cases, and relapsed cases.

Results 

The success rates of both used drug regimens were comparable, with the rate of success of TMX-Doxy combination being 90%, whereas it was 94% in the RIF-Doxy group (P=0.23). The failure rate was 4% in the TMX-Doxy group and 2% in the RIF-Doxy group (P=0.31). Relapse of brucellosis was recorded in 6% of patients in the TMX-Doxy group, whereas it was 4% of patients in the RIF-Doxy group (P=0.32). The adverse effects of both drug combinations were mild and self-limited, and none of the enrolled patients needed to stop treatment.

Conclusion 

Combination of TMX-Doxy is effective, safe, and not inferior to the more used RIF-Doxy combination.

Introduction

Brucellosis is one of the most common endemic zoonotic diseases worldwide. It is caused by gram-negative coccobacilli belonging to the genus Brucella [¹]. Brucellamelitensis and Brucellaabortus are the most important Brucella spp., primarily infecting small ruminants (sheep and goats) and cattle, respectively [²]. Humans are considered incidental hosts that can be infected through contact with animals and animal products [¹]. Acute infection manifests as a disabling flu-like syndrome with nonspecific clinical signs, including an undulating fever, sweating, chills, myalgia, arthralgia, and fatigue [³]. Single-agent therapy with drugs such as cotrimoxazole, doxycycline, rifampicin, and ciprofloxacin has been abandoned owing to the high relapse rates, and a combination of two drug regimens is preferred [⁴]. Multiple drug combinations are used in brucellosis treatment. The combination of doxycycline plus rifampicin for 6 weeks is the most used regimen. Other alternatives include a combination of doxycycline plus trimethoprim-sulfamethoxazole, or a fluoroquinolone plus rifampicin [⁵]. Failure of treatment and relapse after treatment is common, varying from 5 to 15% in mild cases. In the last decade, resistance to Brucella treatment has emerged in brucellosis-endemic regions worldwide (such as Malaysia, Egypt, Qatar, and China) [⁶]. Shevtsov et al. [⁷] reported in their study that resistance to rifampicin is prevalent in Kazakhstan, and about half of the isolates were rifampicin resistant (including the intermediate resistance). Elbehiry et al. [⁸] also observed resistances to ampicillin, ampicillin-sulbactam, and rifampicin in Saudi Arabia. Rifampicin is one of the cornerstones in the treatment of tuberculosis. Moreover, With the emergence of multiresistant strains of mycobacteria, there is an increased need for rifampicin-free regimens in the treatment of brucellosis. Streptomycin is effective in the treatment of brucellosis but still carries the risk of nephrotoxicity and ototoxicity. In addition, parenteral intake is a challenge in some village areas where health facilities are deficient. The combination of doxycycline with trimethoprim-sulfamethoxazole is a possible solution for these obstacles [⁹].

In this study, we aimed to compare the efficacy of two drug regimens used for the treatment of brucellosis: doxycycline plus trimethoprim-sulfamethoxazole (TMX-Doxy) versus doxycycline plus rifampicin (RIF-Doxy) in Egyptian patients.

Patients and methods

Patient’s selection and study settings

This is a prospective study that was carried out in the Department of Tropical Medicine and Gastroenterology, Assiut University, between June 2020 and January 2022. A total of 100 consecutive patients with brucellosis who attended our outpatient clinic and inpatient ward were enrolled in our study. Exclusion criteria were complicated localized brucellosis (spondylitis, endocarditis, and meningoencephalitis), age less than 18 years, pregnancy, receiving antibiotics for more than 1 week before enrollment, and having COVID-19.

For all enrolled patients, the following were done: complete history taking and physical examination, standard tube agglutination test (STAT), complete blood picture, liver enzymes, blood glucose level, erythrocyte sedimentation rate (ESR), C-reactive protein. History taking, clinical examination, and all of these investigations were done before starting treatment, 2, 4 weeks, at the end of treatment, 3 and 6 months after the end of treatment. STAT was done at baseline, at the end of treatment, 3 months after, and 6 months after the end of treatment. Diagnosis was based on a positive STAT result more than or equal to 1/160 association with compatible clinical findings [¹⁰]. STAT test was done by the same laboratory clinician. Plain antigen of B. abortus S99 (IVRI, Izatnagar) was used. Two-fold serial dilutions (1 : 80 to 1 : 1280) of the sera were prepared in phenol saline, and an equal quantity (0.5 ml) of antigen was added to each tube. All of the tubes were incubated at 37°C for 24 h. The results were compared with the antigen control tube showing 50% agglutination. A titer of 1 : 160 or above was considered positive. Brucellosis was classified into acute (if the duration of illness is <2 months) and chronic (if the duration of illness is more than 2 months) [¹¹]. Half of the enrolled patients randomly received doxycycline plus trimethoprim-sulfamethoxazole, whereas the other half received doxycycline plus rifampicin. The two regimens were given for 6 weeks. Randomization was done by writing 100 cards. Overall, 50 of them were assigned to the first group that received the TMX-Doxy combination, whereas the other 50 were assigned to the group that received the RIF-Doxy combination. The cards were placed in sealed envelopes, and all were mixed. The patient or the treating doctor chose one of the cards to put the patient in the group that was drawn blindly. The dosage of drugs was doxycycline (100 mg twice a day), trimethoprim-sulfamethoxazole (160 mg of trimethoprim plus 800 mg of sulfamethoxazole twice a day), and rifampicin (600 mg per day) [⁶].

Study definitions [¹²]

Successful treatment was defined by subsiding fever, back pain, and sweating with or without decline in STAT titer.

Relapse was diagnosed when the clinical manifestations reappeared and titer of STAT re-increase again after its reduction.

Therapeutic failure was defined by persistence of symptoms (fever, sweating or back pain) at the end of treatment with persistently high STAT titer.

Statistical analysis

The data in the two groups were collected and analyzed using the Statistical Package for the Social Sciences (version 21; SPSS Inc., Chicago, Illinois, USA). Data were presented as numbers, percentages, means, and SDs. The χ² test was used to compare the therapeutic effect of two regimens. Overall, 95% confidence intervals were calculated when appropriate. Difference with a P value of less than 0.05 was considered significant.

Ethical consideration and funding

The study protocol was approved by the ethics committee of the Faculty of Medicine, Assiut University (IRB No. 17300850), and was adherent to the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from each participant. The study was registered at pactr.samrc.ac.za (PACTR202210778524094).

Results

Basic clinical and imaging characteristics

Table 1 shows the clinical data and abdominal ultrasound findings. A total of 100 patients with acute and chronic brucellosis were involved in our study. Overall, 50 patients, with a mean age of 39.3±15.23 years, was treated with TMX-Doxy group, and 50 patients, with a mean age of 38.1±14.8 years, were treated with rifampicin plus doxycycline RIF-Doxy group. Male sex was predominant in both groups (71 males versus 29 females). The most observed symptom was fever, followed by sweating. Acute brucellosis was diagnosed in 77 patients, whereas chronic brucellosis was diagnosed in 23 patients in both groups.

Table 1: Basic clinical and imaging characteristics of the studied groups

Table 2 shows the laboratory investigations of the patients. Leukocytosis was observed in 13 (13%) patients of all patients in the two groups, whereas leukopenia was observed in three (3%) of the 100 patients. Anemia was present in 18 (18%) patients in both groups. Thrombocytosis was recorded in three (3%) patients only. Erythrocyte sedimentation rate was raised in 19 (19%) patients and C-reactive protein was positive in 68 (68%) patients. STAT was positive with variable titers. The most observed titers were 1/160 and 1/320. For five of the 100 patients, higher dilutions were requested when the initial STAT was negative but still clinically suspected cases to avoid the prozone phenomenon and the test was positive with 1/1280 dilution.

Table 2: Laboratory data of the studied groups

Outcomes of treatment

Successful treatment (disappearance of symptoms and no relapse within 6 months of treatment) was recorded in 45 (90%) patients of the TMX-Doxy group, whereas it was seen in 47 (94%) patients in the RIF-Doxy group, with no statistically significant difference between the two groups. Failure of treatment was observed in two (4%) patients in the TMX-Doxy group and one (2%) patient in the RIF-Doxy group. Relapse of brucellosis was recorded in three (6%) cases treated in the TMX-Doxy group, whereas two (4%) cases relapsed treated in the RIF-Doxy group. Table 3 shows the outcomes of treatment.

Table 3: Outcomes of treatment

As shown in Table 4, some adverse effects of the used drugs were reported. All of them were mild and self-limited and did not necessitate stoppage of therapy. Diarrhea, mild hypersensitivity (mild itching and skin rash), and gastrointestinal upset were the most observed adverse effects. Liver injury with mildly raised liver enzymes was detected in only one (2%) patient in the TMX-Doxy group and three (3%) patients in the RIF-Doxy group. Follow-up liver enzymes were normal, and treatment was continued.

Table 4: Adverse effects of the used drugs

Discussion

Brucellosis is still a challenging infectious intracellular zoonotic disease that has both domestic animal and human burden with significant economic losses. Brucellosis is one of the group B notifiable diseases in Egypt. Nevertheless, 50–60% of patients are managed in the primary care private sector [¹³]. Many trials were done to study monotherapy with ciprofloxacin for the treatment of brucellosis, but relapse rate was high in all of these studies [^14,15]. Therefore, combination therapy is now recommended for at least 6 weeks, with rifampicin-based combination antibiotics are still the most recommended and most used regimens [^15,16].

Communities, like Egypt, with high prevalence of tuberculosis suffer from emerging of resistant strains of tuberculosis, may be partly due to overuse of rifampicin in the treatment of brucellosis, especially in villages where both brucellosis and tuberculosis are prevalent [^17,18,19]. Other alternative regimens have been suggested and studied for the treatment of brucellosis to avoid using rifampicin and reserve it for tuberculosis. One of the suggested regimens was TMX-Doxy Combination for 6 weeks. Few previous studies have evaluated this regimen [^20,21]. In our study, we aimed to compare two regimens in the treatment: TMX-Doxy in comparison with rifampicin plus doxycycline.

Our results showed that the TMX-Doxy combination is highly effective in the treatment of brucellosis with a success rate of 90%. This is comparable to the success rate of the other regimen (RIF-Doxy combination), which has a 94% success rate in our study.

These results confirm the high efficacy of both TMX-Doxy and RIF-Doxy combinations. In contrast with our results, Alavi et al. [²⁰] reported a higher efficacy of the TMX-Doxy group over the RIF-Doxy combination (92.15 vs. 78.43%) with significant differences between the two regimens.

In another older study, Roushan et al. [²¹] reported that the efficacy of TMX-Doxy combination was 84.3%, which was higher than the TMX-RIF combination (73.6%).

Regarding failure of therapy, in our study, we found only two (4%) cases in the TMX-Doxy group versus only one (2%) case in the RIF-Doxy group. This is comparable to the results of Alavi and Rajabzadeh [²⁰], who reported a 1.94% failure rate in the TMX-Doxy group.

In contrast to our study, Roushan et al. [²¹] reported a higher failure rate of treatment with the TMX-Doxy combination (7.1%). This may be explained by the larger sample size in their study.

Regarding relapse of brucellosis after treatment, we diagnosed three (6%) patients in the TMX-Doxy group and two (4%) patients in the RIF-Doxy group. Alavi and Rajabzadeh [²⁰] found slightly higher rate of relapse (5.88% in the TMX-Doxy group and 11.76% in the RIF-Doxy group). The same results were obtained in the study by Roushan et al. [²¹], who reported an 8.6% relapse rate in the TMX-Doxy group.

The reported adverse effects of the used drugs in our study were all mild and self-limited. None of them necessitated stoppage of treatment. Gastrointestinal upset, diarrhea, mild skin allergy, and mild liver injury were observed after 2 weeks of treatment and improved at the second follow-up after 1 month of treatment.

In areas where brucellosis is endemic, tuberculosis may also be common. Trials to avoid use of rifampicin and use of other drug combinations should be made to decrease the rate of emerging resistant strains of TB. In our study, we found that the combination of TMX-Doxy was highly effective and safe with low rate of relapse and failure of treatment. It is tolerable with no serious adverse effects.

In conclusion, both regimens (TMX-Doxy and RIF-Doxy) are effective in treating brucellosis. Both regimens are also safe with no major adverse effects encountered. We recommend the TMX-Doxy combination as an effective and safe alternative combination to the RIF-Doxy combination to save rifampicin for patients with tuberculosis to decrease the incidence of drug-resistant mycobacteria.

Limitations

In our study, the sample size was relatively small, so the number of cases that failed to response or relapsed was too small to compare in the acute or chronic stages. Therefore, we recommend a larger study to assess the risk factors for failure of treatment or relapse.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgements

Author’s contributions: Waleed Attia Hassan conceived and designed the experiments. Waleed Attia Hassan, Muhammad Abdel-Gawad, and Ahmed Shawkat performed the experiments. Waleed Attia Hassan and Muhammad Abdel-Gawad performed the data analysis, data accuracy, data validation, statistical analysis, investigation, and supervision. Waleed Attia Hassan and Ahmed Shawkat drafted the manuscript. Waleed Attia Hassan and Muhammad Abdel-Gawad wrote, reviewed, and edited the article. All authors have read and agreed to the published version of the manuscript.