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Acinetobacter baumannii is a notorious opportunistic pathogen responsible for healthcare-associated infections worldwide. Efflux pumps play crucial roles in mediating antimicrobial resistance, motility, and virulence. In this study, we present the identification and characterization of the new A. baumannii efflux pump SxtP belonging to the MFS superfamily (major facilitator superfamily), along with its associated activator LysR-type transcriptional regulator (LTTR) SxtR, demonstrating their roles in sulfamethoxazole/trimethoprim (also known as co-trimoxazole or SXT) resistance, surface-associated motility and virulence.

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Background: Co-trimoxazole is used as a prophylaxis for human immunodeficiency virus (HIV) patients to prevent opportunistic infections. Its widespread use results in the emergence of co-trimoxazole resistance, which is a significant problem. This systematic review and meta-analysis determined the pooled prevalence of co-trimoxazole resistance among HIV-infected individuals in Ethiopia. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was applied to report this study. The protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the assigned number CRD42024532240. Article search was performed using electronic databases such as PubMed, Medline, EMBASE, Google Scholar, Hinari, Web of Science, Science Direct, and African Journals Online. Data were extracted using a Microsoft Excel spreadsheet and analyzed using STATA version 11.0 software. A random-effects model was used to estimate the pooled effect size of co-trimoxazole resistance across studies with a 95% confidence interval. The heterogeneity was checked using I2 statistic. The presence of publication bias was determined using a funnel plot and Egger's test with a p-value <0.05 evidence of statistically significant bias. Subgroup and sensitivity analyses were performed. Results: Twenty-two studies with 5,788 HIV-infected individuals were included. The pooled prevalence of co-trimoxazole resistance was 61.73% (95% CI: 53.10-70.37%), with heterogeneity (I2 = 87.7%) and statistical significance (p < 0.001). A higher co-trimoxazole resistance was observed in HIV-infected individuals with urinary tract infection; 82.10% (95% CI: 75.03-89.17%). Among the bacterial spp., higher resistance to co-trimoxazole was observed in Escherichia coli; 70.86% (95% CI: 53.44-88.27%) followed by Salmonella spp.; 67.66% (95% CI: 41.51-93.81%) and Proteus spp.; 66.23% (95% CI: 34.65-97.82%). Conclusion: There is a higher prevalence of co-trimoxazole resistance in HIV-infected individuals in Ethiopia. This alarms WHO's recommendation of co-trimoxazole prophylaxis guidelines to review and update it. Additionally, a nationwide assessment of co-trimoxazole resistance in Ethiopia as a whole is required.Systematic review registration: identifier: CRD42024532240.

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Receipt of nebulised pentamidine in people with HIV was audited to identify if individuals were appropriately receiving nebulised pentamidine, and whether national guidelines were being followed when prophylaxis was commenced and discontinued. Of 76 people with who received nebulised pentamidine, the main indication for starting nebulised pentamidine was a co-trimoxazole adverse drug reaction. Co-trimoxazole desensitization was not attempted before starting nebulised pentamidine. The main indication for stopping nebulised pentamidine prophylaxis was when immune reconstitution occurred. This single centre audit revealed that national guidelines were being followed in most cases. The lack of information regarding the reason for starting or stopping nebulised pentamidine prophylaxis, or detail of the clinician's concerns about potential poor adherence with oral regimens of prophylaxis as a reason for choosing nebulised pentamidine prophylaxis, identifies a need for improved documentation of clinicians' decision-making. Introduction of pharmacist-led interventions/alerts using patients' electronic records, similar to those used in primary care, would enable the specialist pharmacy team to identify when and if co-trimoxazole desensitization has been offered and discussed/declined before a clinician prescribes nebulised pentamidine as well as enabling identification of those in who pentamidine prophylaxis has been continued, despite "immune reconstitution".

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Trimethoprim-sulfamethoxazole (TMP-SMX) is a broad spectrum antibiotic in use for more than 50 years. It has an important indication as first line agent in the prophylaxis of opportunistic infections, particularly Pneumocystis jirovecii pneumonia (PJP), in immunosuppressed patients. For those who have a history of allergy or severe intolerance to TMP-SMX, pentamidine, dapsone or atovaquone may be substituted; however there is evidence that TMP-SMX offers superior coverage for PJP, toxoplasmosis, and nocardiosis. Compared to pentamidine, it has the added benefit of cost-effectiveness and self-administration as opposed to required hospital attendance for administration. Many patients who report a history of allergy or adverse reaction to TMP-SMX (or "sulfur allergy") will be found not to be allergic; and even those who are allergic may be able to be desensitized. The evaluation and, where appropriate, removal of TMP-SMX allergy label enables the use of TMP-SMX for prophylaxis against opportunistic infections. This is a cost-effective intervention to optimize antimicrobial prescribing and reduce the risk of opportunistic infections in immunosuppressed patients.

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Haemophagocytic lymphohistiocytosis (HLH) is a rare, aggressive, excess immune activation syndrome. Diagnosis can be challenging due to its several clinical mimics including sepsis. There are multiple aetiologies of HLH; in adults, it is most commonly triggered by infection, malignancy, drugs and autoimmune processes. Failure to rapidly diagnose and treat this condition can be fatal. The management of HLH includes identifying and removing the trigger, supportive management and immunosuppression. Identifying the trigger is essential to inform the most appropriate type of immunosuppression. Here, we report a case of likely drug-induced HLH in a patient recently treated for hairy cell leukaemia. The culprit drug was thought to be co-trimoxazole and this case report highlights a very rare complication of this commonly used drug. We discuss our management approach with steroid monotherapy and withdrawal of co-trimoxazole.

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To assess the effect of co-trimoxazole and N-acetylcysteine (NAC), alone and in combination, on bacterial adherence to biofilm formed on ureteral stent surfaces. This prospective randomized study was conducted on 636 patients who underwent double J ureteral stent insertion after variable urological procedures. Patients were randomized into four groups: A (n = 165), no antibiotics or mucolytics during stent indwelling; B (n = 153), oral NAC (200 mg/day for children aged < 12 years old and 600 mg/day for adults) during stent indwelling; C (n = 162), oral co-trimoxazole (2 mg TMP/kg/day) during stent indwelling; and D (n = 156), both oral NAC and co-trimoxazole during stent indwelling. Two weeks following double J stent (JJ stent) insertion, urinalysis was performed on all patients and urine culture was done for all the patients at the day of double J stent removal. The stent was removed 2 weeks postoperatively, and a stent segment sized 3-5 cm from the bladder segment of the stent was sent for culture. Positive stent cultures were found in 63.6% (105/165), 43.1% (66/153), 37% (60/162), and 19.2% (30/156) patients of groups A, B, C, and D, respectively. E. coli was the organism most commonly isolated from the stent culture in all groups. The combination of co-trimoxazole and NAC was more effective in reducing bacterial adherence on ureteral stent surfaces than either alone.

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Introduction: Burkholderia pseudomallei is the bacterium that causes melioidosis. It is mostly a tropical disease, and particularly common in Southeast Asia and northern Australia. The intensive intravenous phase and the oral prolonged eradication phase are the two phases of melioidosis treatment. The current recommended treatment for melioidosis eradication is oral co-trimoxazole (TMP/SMX). Case report: Two patients were diagnosed with B. pseudomallei bacteremia without a focus and were treated with oral TMP/SMX with folic acid during the eradication phase. Both presented with neutropenic sepsis with pneumonia and pyelonephritis at days 48 and 45 following TMP/SMX 320/1600 mg q12h (4 tablets) and in both of them, the folic acid compliance was poor. One patient died and the other survived following intensive treatment for neutropenia. At the presentation following neutropenic sepsis among both patients, the red blood cells and platelets were within normal limits. Both patients were on a high dose of TMP/SMX, as both were within 40-60 kg of body weight the ideal TMP/SMX dose would be 240/1200 mg q12h (3 tablets). Pancytopenia caused by TMP/SMX can frequently develop gradually over time. Alternately, it can develop rapidly and swiftly escalate to fulminant sepsis, disseminated intravascular coagulation, and fast hemolysis. However, the development of isolated neutropenia is rarely described in the literature. Conclusions: Prolonged use of TMP/SMX is important to eradicate B. pseudomallei and always the possibility of rare adverse effects has to be considered. Always weight-based TMP-SMX dosing has to be encouraged with need to ensure the compliance of folic acid. During the eradication phase, continuous monitoring of blood cell lines with weekly full blood count would be essential to identify neutropenia in advance.

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BACKGROUND: Infections caused by Stenotrophomonas maltophilia (S. maltophilia) and Pneumocystis jirovecii (Pneumocystis jirovecii pneumonia (PJP)) require weight-based dosing for co-trimoxazole. The aim of this study is to assess the appropriateness of co-trimoxazole dosing in adult inpatients for the treatment of these infections. METHODOLOGY: This is a single-center, cross-sectional study that included adult inpatients treated with co-trimoxazole for a weight-based dose indication (S. maltophilia and PJP). The primary outcome was the appropriateness of co-trimoxazole dosing for these infections. RESULTS: Forty-three patients were included in the study. Of the 43 patients, 29 (67.4%) were using co-trimoxazole for PJP treatment, and 14 (32.6%) were using it for S. maltophilia treatment. The co-trimoxazole dose was appropriate in 22 (51.2%) patients, 21 (72.4%) in the PJP treatment group, and one (7.1%) in the S. maltophilia treatment group. Underdosing was observed in 21 (48.8%) patients, of whom eight (27.6%) were in the PJP treatment group and 13 (92.9%) were in the S. maltophilia treatment group. CONCLUSIONS: This study found a relatively high rate of underdosing of co-trimoxazole based on weight in hospitalized adults with PJP and S. maltophilia infections.

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Studies found a strong association between HLA-B*13:01 allele and co-trimoxazole-induced severe cutaneous adverse reactions (SCARs). Genetic screening before initiation of co-trimoxazole may decrease the incidence of co-trimoxazole-induced SCARs. This study aims to evaluate the cost-effectiveness of HLA-B*13:01 screening before co-trimoxazole initiation in HIV-infected patients in Thailand. A combination of a decision tree model and a Markov model was used to estimate lifetime costs and outcomes of two strategies including 1) HLA-B*13:01 screening before co-trimoxazole initiation and 2) usual practice from a societal perspective. Alternative drugs are not considered because dapsone (the second-line drug) also presents a genetic risk. Input parameters were obtained from literature, government documents, and part of the TREAT Asia HIV Observational Database (TAHOD). One-way sensitivity analyses and probabilistic analyses were performed to determine robustness of the findings. HLA-B*13:01 screening resulted in 0.0061 quality-adjusted life years (QALYs) loss with an additional cost of 370 THB ($11.84). At the cost-effectiveness threshold of 160,000 THB ($5,112.85), the probability of the genetic screening strategy being cost-effective is 9.54%. This analysis demonstrated that HLA-B*13:01 allele screening before initiation of co-trimoxazole among HIV-infected patients is unlikely to be cost-effective in Thailand. Our findings will help policymakers make an evidence-informed decision making.

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BACKGROUND: Co-trimoxazole has been reported as a common culprit drug for various cutaneous adverse drug reactions (CADRs). However, information on genotypic and phenotypic characteristics is still limited. We aimed to study clinical characteristics, genetic suitability, laboratory findings, and treatment outcomes in patients with co-trimoxazole-induced CADR and determine variables associated with severe cutaneous adverse reactions (SCARs). METHODS: The medical records of all patients diagnosed with co-trimoxazole-induced CADR during October 2015 and October 2021 were reviewed. Clinical characteristics and laboratory investigation with an emphasis on human leukocyte antigen (HLA) class I and HLA-DRB1 results linked to subtypes of cutaneous adverse reactions were evaluated. RESULTS: Seventy-two patients diagnosed with co-trimoxazole-induced CADR were included in the study. Mean age at diagnosis was 38.0 ± 14.6 years old, and 72% were female. Subtypes of reactions included maculopapular eruption (MPE; 56.9%), drug reaction with eosinophilia and systemic symptoms (DRESS; 23.6%), Stevens-Johnson syndrome (SJS; 12.5%), fixed drug eruption (4.2%), and urticaria (2.8%). Characteristics that were significantly associated with SCARs included male gender (OR = 3.01, 95% CI: 1.04-8.75), HIV infection (OR = 3.48, 95% CI: 1.13-10.75), prophylactic use of co-trimoxazole (OR = 4.89, 95% CI: 1.54-15.57), and co-trimoxazole administration longer than 10 days (OR = 7.65, 95% CI: 2.57-22.78). HLA-B*38:02 was associated with co-trimoxazole-induced SJS, while HLA-A*11:01, HLA-B*13:01, and HLA-DRB1*12:01 were associated with co-trimoxazole-induced DRESS. HLA-B*52:01 was associated with co-trimoxazole-induced MPE. CONCLUSIONS: Co-trimoxazole could induce various phenotypes of CADRs. Genotypic and phenotypic factors that may potentially predict co-trimoxazole-induced SCARs include male gender, HIV infection, prophylactic and prolonged drug use, as well as the presence of HLA-A*11:01, HLA-B*13:01, HLA-B*38:02, or HLA-DRB1*12:01 alleles.

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BACKGROUND: Melioidosis is an infectious disease caused by the bacterium Burkholderia pseudomallei. The two stages of melioidosis treatment are the intense intravenous phase and the oral eradication phase. Although co-trimoxazole has been in use for several years, the literature does not demonstrate uniformity of the drug doses, combinations, or durations suitable for the eradication phase of melioidosis. The safety profile of co-trimoxazole was not documented in the literature, nor have systematic studies of its effectiveness been done. This systematic review sought to study on the dose, duration and combination of co-trimoxazole therapy in view of clinical efficacy and safety in the eradication phase of melioidosis. MAIN BODY: This systematic review included all of the published articles that employed co-trimoxazole in the eradication phase after 1989, including, randomized clinical trials, case-control studies, cohorts, case reports, and case series. Throughout the eradication (maintenance) phase, co-trimoxazole usage was permissible in any dose for any period. A total of 40 results were included in the analysis which contained six clinical trials, one cohort study, one Cochrane review, and thirty-two case series/case reports. Clinical and microbial relapse rates are low when co-trimoxazole is used in single therapy than in combination. There were several adverse events of co-trimoxazole, however, a quantitative analysis was not conducted as the data did not include quantitative values in most studies. SHORT CONCLUSION: The dose of co-trimoxazole, duration of the eradication phase, and other combinations used in the treatment was varying between studies. Compared to combined therapy patients treated with co-trimoxazole alone the mortality and relapse rates were low. The lowest relapse rate and lowest mortality rate occur when using co-trimoxazole 1920 mg twice daily. The duration of therapy varies on the focus of melioidosis and it is ranged from 2 months to one year and minimum treatment duration associated with low relapse rate is 3 months. The use of co-trimoxazole over the maintenance phase of melioidosis is associated with clinical cure but has adverse effects.

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Purpose: Stenotrophomonas maltophilia, a multidrug-resistant pathogen can cause hospital-acquired infections such as pneumonia, or bloodstream infection. S. maltophilia infection is associated with high mortality rates. This retrospective study examined the antimicrobial susceptibility profile of clinical S. maltophilia isolates and evaluated clinical outcomes, treatment regimens, and risk factors associated with 30-day mortality or treatment failure of S. maltophilia infections at three tertiary care hospitals in Central Thailand. Patients and Methods: The characteristics, microbiological data, and clinical treatment outcomes were derived from medical records obtained from three tertiary care hospitals in Central Thailand from January 2017 to October 2022. The primary outcomes were treatment failure and 30-day mortality. The antimicrobial susceptibility rates of trimethoprim-sulfamethoxazole (TMP-SMX), levofloxacin, and ceftazidime were determined by minimum inhibitory concentration (MIC), which were based on broth microdilution and clear zone diameters using the disk diffusion method. However, we also report the susceptibility of minocycline and tigecycline in some clinical S. maltophilia strains (n = 149) and determined by MIC with E-test method. Results: The antimicrobial susceptibility rates to TMP-SMX, levofloxacin, and ceftazidime were 97.1%, 93%, and 55.3%, respectively. The treatment failure rate and 30-day mortality were 66.3% and 49%, respectively. Significant factors associated with treatment failure included APACHE II score ≥15 (OR 3.37, 95% confidence interval (CI) 1.46-7.76), polymicrobial infections (OR 3.20, 95% CI 1.35-7.55). The significant factors associated with reduced treatment failure was treatment with TMP-SMX-based regimen (OR 0.29, 95% CI 0.11-0.76). The 30-day mortality rate was associated with APACHE II score ≥15 (OR 3.27, 95% CI 1.45-7.39) and septic shock (OR 2.53, 95% CI 1.36-4.69). Conclusion: The results indicate a high mortality rate for S. maltophilia infection. The predictive factors for an unfavourable outcome were severity of illness, septic shock, and non-use of TMP-SMX. Therefore, a TMP-SMX-based regimen is recommended for the treatment of S. maltophilia infections.

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INTRODUCTION: Co-trimoxazole prophylaxis is recommended for children born to women with HIV to protect those who acquire HIV from opportunistic infections, severe bacterial infections and malaria. With scale-up of maternal antiretroviral therapy, most children remain HIV-exposed uninfected (HEU) and the benefits of universal co-trimoxazole are uncertain. We assessed the effect of co-trimoxazole on mortality and morbidity of children who are HEU. METHODS: We performed a systematic review (PROSPERO number: CRD42021215059). We systematically searched MEDLINE, Embase, Cochrane CENTRAL, Global Health, CINAHL Plus, Africa-Wide Information, SciELO and WHO Global Index Medicus for peer-reviewed articles from inception to 4th January 2022 without limits. Ongoing randomized controlled trials (RCTs) were identified through registries. We included RCTs reporting mortality or morbidity in children who are HEU receiving co-trimoxazole versus no prophylaxis/placebo. The risk of bias was assessed using the Cochrane 2.0 tool. Data were summarized using narrative synthesis and findings were stratified by malaria endemicity. RESULTS: We screened 1257 records and included seven reports from four RCTs. Two trials from Botswana and South Africa of 4067 children who are HEU found no difference in mortality or infectious morbidity in children randomized to co-trimoxazole prophylaxis started at 2-6 weeks of age compared to those randomized to placebo or no treatment, although event rates were low. Sub-studies found that antimicrobial resistance was higher in infants receiving co-trimoxazole. Two trials in Uganda investigating prolonged co-trimoxazole after breastfeeding cessation showed protection against malaria but no other morbidity or mortality differences. All trials had some concerns or a high risk of bias, which limited the certainty of evidence. DISCUSSION: Studies show no clinical benefit of co-trimoxazole prophylaxis in children who are HEU, except to prevent malaria. Potential harms were identified for co-trimoxazole prophylaxis leading to antimicrobial resistance. The trials in non-malarial regions were conducted in populations with low mortality potentially reducing generalizability to other settings. CONCLUSIONS: In low-mortality settings with few HIV transmissions and well-performing early infant diagnosis and treatment programmes, universal co-trimoxazole may not be required.

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Cerebral toxoplasmosis is a rare condition that predominantly affects immunocompromised people and is relatively uncommon in immunocompetent individuals. Acute toxoplasmosis primarily presents with focal and diffuse neurological signs and symptoms depending on the site of the lesion, the degree of local damage, and the severity of inflammation. In this report, we present a case of cerebral toxoplasmosis in an immunocompetent adult female who presented with an altered level of consciousness, fever, headache, and shortness of breath. This case highlights the diagnostic challenges that may arise when dealing with patients who have a wide range of clinical manifestations.

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@#Vibrio cholerae is a gram-negative bacterium synonymous with its namesake disease, cholera. Thus, gastrointestinal symptoms are the norm and V. cholerae is very rarely associated with skin and soft tissue infections. We describe a case of a 63-year-old Chinese woman with multiple medical comorbidities on corticosteroid therapy who developed fever and a painful swelling on her left leg after being pricked by a branch while gardening. There was no abdominal pain, vomiting or diarrhea. A diagnosis of bullous cellulitis was made clinically, and blood was sent for bacteriological culture. A beta-hemolytic commashaped gram-negative bacillus was isolated from the blood. It was also oxidase-positive and produced an acid/alkaline (A/K) reaction on triple sugar iron agar. It was identified biochemically as Vibrio cholerae. After additional testing, it was found to be of the O1 serogroup and Ogawa serotype. The infection resolved following a 10-day course of high-dose co-trimoxazole therapy.

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Burkholderia mallei, the causative agent of glanders, is principally a disease of equines, although it can also infect humans and is categorized by the U.S. Centers for Disease Control and Prevention as a category B biological agent. Human cases of glanders are rare and thus there is limited information on treatment. It is therefore recommended that cases are treated with the same therapies as used for melioidosis, which for prophylaxis, is co-trimoxazole (trimethoprim/sulfamethoxazole) or co-amoxiclav (amoxicillin/clavulanic acid). In this study, the fluoroquinolone finafloxacin was compared to co-trimoxazole as a post-exposure prophylactic in a murine model of inhalational glanders. BALB/c mice were exposed to an aerosol of B. mallei followed by treatment with co-trimoxazole or finafloxacin initiated at 24 h post-challenge and continued for 14 days. Survival at the end of the study was 55% or 70% for mice treated with finafloxacin or co-trimoxazole, respectively, however, this difference was not significant. However, finafloxacin was more effective than co-trimoxazole in controlling bacterial load within tissues and demonstrating clearance in the liver, lung and spleen following 14 days of therapy. In summary, finafloxacin should be considered as a promising alternative treatment following exposure to B. mallei.

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Co-trimoxazole is mainly used as a first-line drug for treatment and prophylaxis against Pneumocystis jiroveci pneumonia. This drug, however, has been reported as the most common causative drug for severe cutaneous adverse reactions (SCARs). This study aimed to extensively elucidate the associations between genetic polymorphisms of HLA class I and genes involved in bioactivation and detoxification of co-trimoxazole on co-trimoxazole-induced SCARS in a large sample size and well-defined Thai SCARs patients. A total of 67 patients with co-trimoxazole-induced SCARs, consisting of 51 SJS/TEN patients and 16 DRESS patients, and 91 co-trimoxazole tolerant controls were enrolled in the study. The results clearly demonstrated that the HLA-B∗13:01 allele was significantly associated with co-trimoxazole-induced SCARs, especially with DRESS (OR = 8.44, 95% CI = 2.66-26.77, P = 2.94 × 10-4, Pc = 0.0126). Moreover, the HLA-C∗08:01 allele was significantly associated with co-trimoxazole-induced SJS/TEN in the HIV/AIDS patients with an OR of 8.51 (95% CI = 2.18-33.14, P = 8.60 × 10-4, Pc = 0.0241). None of the genes involved in the bioactivation and detoxification of co-trimoxazole investigated in this study play any major role in the development of all phenotypes of SCARs.

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Burkholderia pseudomallei is the causative agent of melioidosis, a multifaceted disease. A proportion of the mortality and morbidity reported as a result of infection with this organism may be due to the premature cessation of antibiotic therapy typically lasting for several months. The progression of re-emergent disease was characterised in Balb/c mice following cessation of a 14 day treatment course of co-trimoxazole or finafloxacin, delivered at a human equivalent dose. Mice were culled weekly and the infection characterised in terms of bacterial load in tissues, weight loss, clinical signs of infection, cytokine levels and immunological cell counts. Following cessation of treatment, the infection re-established in some animals. Finafloxacin prevented the re-establishment of the infection for longer than co-trimoxazole, and it is apparent based on the protection offered, the development of clinical signs of disease, bodyweight loss and bacterial load, that finafloxacin was more effective at controlling infection when compared to co-trimoxazole.