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There are limited data on the role of antimicrobials in the treatment of skin abscesses. In this trial, clindamycin or trimethoprim–sulfamethoxazole was found to facilitate more rapid resolution than placebo in the management of skin abscess under 5 cm in diameter. More than 4 in 100 people seek treatment for skin infections annually in the United States. 1 Abscesses are the most common of these infections, and the majority of patients are treated as outpatients. 1 Serious complications, such as bacteremia, occur in rare cases. 1 , 2 Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains, causes most skin infections, 3 , 4 but the appropriate strategy for the treatment of these infections has not been defined. Clindamycin and trimethoprim–sulfamethoxazole (TMP-SMX) are recommended for outpatient treatment of abscesses because of their low cost and in vitro activity against community-associated MRSA and methicillin-susceptible strains, 5 but data on their . . .

The cornerstone of malaria prevention in pregnancy, intermittent preventive treatment (IPTp) with sulfadoxine–pyrimethamine, is contraindicated in women with HIV who are receiving co-trimoxazole prophylaxis. We assessed whether IPTp with dihydroartemisinin–piperaquine is safe and effective in reducing the risk of malaria infection in women with HIV receiving co-trimoxazole prophylaxis and antiretroviral drugs. For this randomised, double-blind, placebo-controlled clinical trial, women with HIV attending the first antenatal care clinic visit, resident in the study area, and with a gestational age up to 28 weeks were enrolled at five sites in Gabon and Mozambique. Participants were randomly assigned (1:1) to receive either IPTp with dihydroartemisinin–piperaquine at each scheduled antenatal care visit plus daily co-trimoxazole (intervention group) or placebo at each scheduled antenatal care visit plus daily co-trimoxazole (control group). Randomisation was done centrally via block randomisation (block sizes of eight), stratified by country. IPTp was given over 3 days under direct observation by masked study personnel. The number of daily IPTp tablets was based on bodyweight and according to the treatment guidelines set by WHO (target dose of 4 mg/kg per day [range 2–10 mg/kg per day] of dihydroartemisinin and 18 mg/kg per day [range 16–27 mg/kg per day] of piperaquine given once a day for 3 days). At enrolment, all participants received co-trimoxazole (fixed combination drug containing 800 mg trimethoprim and 160 mg sulfamethoxazole) for daily intake. The primary study outcome was prevalence of peripheral parasitaemia detected by microscopy at delivery. The modified intention-to-treat population included all randomly assigned women who had data for the primary outcome. Secondary outcomes included frequency of adverse events, incidence of clinical malaria during pregnancy, and frequency of poor pregnancy outcomes. All study personnel, investigators, outcome assessors, data analysts, and participants were masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT03671109. From Sept 18, 2019, to Nov 26, 2021, 666 women (mean age 28·5 years [SD 6·4]) were enrolled and randomly assigned to the intervention (n=332) and control (n=334) groups. 294 women in the intervention group and 308 women in the control group had peripheral blood samples taken at delivery and were included in the primary analysis. Peripheral parasitaemia at delivery was detected in one (<1%) of 294 women in the intervention group and none of 308 women in the control group. The incidence of clinical malaria during pregnancy was lower in the intervention group than in the control group (one episode in the intervention group vs six in the control group; relative risk [RR] 0·12, 95% CI 0·03–0·52, p=0·045). In a post-hoc analysis, the composite outcome of overall malaria infection (detected by any diagnostic test during pregnancy or delivery) was lower in the intervention group than in the control group (14 [5%] of 311 women vs 31 [10%] of 320 women; RR 0·48, 95% CI 0·27–0·84, p=0·010). The frequency of serious adverse events and poor pregnancy outcomes (such as miscarriages, stillbirths, premature births, and congenital malformations) did not differ between groups. The most frequently reported drug-related adverse events were gastrointestinal disorder (reported in less than 4% of participants) and headache (reported in less than 2% of participants), with no differences between study groups. In the context of low malaria transmission, the addition of IPTp with dihydroartemisinin–piperaquine to co-trimoxazole prophylaxis in pregnant women with HIV did not reduce peripheral parasitaemia at delivery. However, the intervention was safe and associated with a decreased risk of clinical malaria and overall Plasmodium falciparum infection, so it should be considered as a strategy to protect pregnant women with HIV from malaria. European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) and Medicines for Malaria Venture. For the Portuguese and French translations of the abstract see Supplementary Materials section.

In this randomized clinical trial in patients presenting to U.S. emergency departments with an acute uncomplicated cutaneous abscess, drainage plus trimethoprim–sulfamethoxazole therapy for a week was associated with modest clinical benefits as compared with drainage alone. Between 1993 and 2005, annual emergency department visits for skin and soft-tissue infections in the United States increased from 1.2 million to 3.4 million, primarily because of an increased incidence of abscesses. 1 , 2 During this period, community-associated methicillin-resistant Staphylococcus aureus (MRSA) emerged as the most common cause of purulent skin and soft-tissue infections in many parts of the world. 3 Trimethoprim–sulfamethoxazole, which has retained in vitro activity against community-associated MRSA, is among the most commonly prescribed antibiotics to treat these infections. 4 The primary treatment of a cutaneous abscess is drainage. 5 Whether adjunctive antibiotics lead to improved outcomes in patients with uncomplicated . . .

ObjectivesTo investigate the efficacy and safety of trimethoprim/sulfamethoxazole (TMP-SMX) as primary prophylaxis for pneumocystis pneumonia (PCP) in patients with rheumatic diseases receiving high-dose steroids.MethodsThe study included 1522 treatment episodes with prolonged (≥4 weeks) high-dose (≥30 mg/day prednisone) steroids in 1092 patients over a 12-year period. Of these, 262 treatment episodes involved TMP-SMX (prophylaxis group) while other episodes involved no prophylaxis (control group). Differences in 1-year PCP incidence and its mortality between the two groups were estimated using Cox regression. To minimise baseline imbalance, propensity score matching was performed and efficacy outcome was mainly assessed in the postmatched population (n=235 in both groups).ResultsDuring a total of 1474.4 person-years, 30 PCP cases occurred with a mortality rate of 36.7%. One non-fatal case occurred in the prophylaxis group. TMP-SMX significantly reduced the 1-year PCP incidence (adjusted HR=0.07(95% CI 0.01 to 0.53)) and related mortality (adjusted HR=0.08 (95% CI 0.0006 to 0.71)) in the postmatched population. The result of the same analysis performed in the whole population was consistent with that of the primary analysis. Incidence rate of adverse drug reactions (ADR) related to TMP-SMX was 21.2 (14.8–29.3)/100 person-years. Only two serious ADRs (including one Stevens-Johnson syndrome case) occurred. The number needed to treat for preventing one PCP (52 (33–124)) was lower than the number needed to harm for serious ADR (131 (55–∞)).ConclusionTMP-SMX prophylaxis significantly reduces the PCP incidence with a favourable safety profile in patients with rheumatic disease receiving prolonged, high-dose steroids.

This study from four Australian centers examined whether low-dose, continuous oral antibiotic therapy would prevent urinary tract infection in children (under the age of 18 years) who had already had one or more microbiologically proven urinary tract infections. Long-term, low-dose trimethoprim–sulfamethoxazole was associated with a modest decrease in the number of urinary tract infections in predisposed children. Long-term, low-dose trimethoprim–sulfamethoxazole was associated with a modest decrease in the number of urinary tract infections in predisposed children. Urinary tract infection is a very common illness in children, affecting 2% of boys and 8% of girls by the age of 7 years. 1 Urinary tract infection is associated with long-term morbidity, with renal damage reported in about 5% of affected children. 2 The observation that urinary tract infection and vesicoureteral reflux are associated with renal damage 3 – 5 led to the standard clinical practice of assessment with voiding cystourethrography for the presence of vesicoureteral reflux in children who had had urinary tract infection 6 , 7 and the administration of daily low-dose antibiotics for many years 8 to prevent further urinary tract infections and . . .

Uncomplicated skin infections are a common outpatient clinical problem. In this randomized, controlled trial, clindamycin and trimethoprim–sulfamethoxazole (TMP-SMX) were compared as outpatient therapy for uncomplicated cellulitis or abscess. Skin and skin-structure infections (hereafter referred to as skin infections) are common conditions among patients seeking medical care in the United States, 1 , 2 accounting for approximately 14.2 million outpatient visits in 2005 1 and more than 850,000 hospital admissions. 3 Skin infections are associated with considerable complications, including bacteremia, the need for hospitalization and surgical procedures, and death. 4 , 5 Results of cultures of skin-infection lesions in the United States have shown that most of the infections are caused by methicillin-resistant Staphylococcus aureus (MRSA), 6 , 7 but the efficacy of various antibiotic regimens in areas where community-associated MRSA is endemic has not been defined. . . .

Background Potentiated sulphonamides, combining trimethoprim (TMP) with a sulphonamide such as sulfadiazine (SDZ) or sulfamethoxazole (SMX), are widely used in canine medicine. The standard 1:5 dose ratio was initially designed to achieve a plasma concentration ratio of approximately 1:19 in humans, considered optimal for antibacterial synergy. However, species differences in pharmacokinetics may influence whether this ratio is achieved and maintained in dogs. Updated pharmacokinetic data based on modern analytical techniques and unbound (active) drug concentrations are lacking. This study aimed to characterise and compare the pharmacokinetics and plasma protein binding of TMP/SDZ and TMP/SMX in dogs. Methods Beagle dogs were administered TMP/SDZ or TMP/SMX intravenously and orally in a crossover design. In addition, TMP was administered orally alone once. Plasma concentrations of TMP, SDZ and SMX were quantified using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC–MS/MS). Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling. Protein binding was determined by ultrafiltration, and free fractions were estimated using linear mixed-effects models. Results Oral bioavailability was high for all compounds (93–97%). TMP exhibited substantially higher clearance (0.44 L/h/kg) and a shorter elimination half-life (4.2 h) than SDZ (0.05 L/h/kg; 7.6 h) and SMX (0.026 L/h/kg; 12.6 h). TMP also showed a markedly larger apparent volume of distribution (2.67 L/kg) compared to the sulphonamides (approximately 0.5 L/kg). Protein binding differed between compounds, with population mean free fractions of 0.50 for SDZ, 0.33 for SMX, and 0.43 for TMP. Following both intravenous and oral administration, the free sulphonamide-to-TMP concentration ratios were only close to the proposed 1:19 ratio during the first hours after dosing. Thereafter, the ratios progressively increased due to the more rapid elimination of TMP. Conclusions TMP/SDZ and TMP/SMX display distinct pharmacokinetic profiles in dogs, particularly with respect to clearance, half-life and protein binding. The commonly used 1:5 dose ratio does not maintain a stable 1:19 free concentration ratio over a 12 h dosing interval. These findings provide clinically relevant pharmacokinetic data to support rational and species-specific use of potentiated sulphonamides in dogs.

Objectives We aimed to evaluate the safety and efficacy of cotrimoxazole for preventing infections in patients with glomerulonephritis (GN) receiving rituximab (RTX) therapy. Study design and methods This single-center, open-label randomized controlled trial enrolled 150 patients with GN who received RTX at Xijing Hospital between October 2022 and December 2023. Participants were randomized 1:1 to either the cotrimoxazole prophylaxis group ( n  = 75) or the non-cotrimoxazole group ( n  = 75). The primary endpoint was the cumulative incidence of infection over a 180-day follow-up period. Secondary endpoints included the incidence of severe infections and the rate of adverse events (AEs) attributed to cotrimoxazole. Intervention All patients received RTX at a dose of 1000 mg intravenously on days 1 and 14. CD19 + B-cell counts were monitored monthly for 6-month post-initial infusion; if CD19 + B cells remained detectable at the 6-month mark, an additional 1000-mg RTX dose was administered. Cotrimoxazole prophylaxis protocol Patients in the intervention group initiated oral cotrimoxazole on the same day as their first RTX infusion, with one tablet daily for seven consecutive days. Prophylaxis was repeated for 7 days following each subsequent RTX infusion, resulting in a total of 14 days of prophylaxis over the study period. The non-cotrimoxazole group They received no cotrimoxazole prophylaxis. Results Over 180 days of follow-up, 8 infectious episodes occurred in 7 patients in the cotrimoxazole group, compared with 19 episodes in 16 patients in the control group. The annualized incidence density of infections (per 100 person-years) was 20.80 (95% CI 11.36–30.24) in the cotrimoxazole group versus 54.83 (95% CI 43.09–66.57) in the control group. The hazard ratio (HR) for the cumulative incidence of infection was 0.39 (95% CI 0.17–0.88; log-rank test, P  = 0.029), indicating a significant reduction in infection risk with cotrimoxazole prophylaxis. Conclusions Our findings demonstrate that cotrimoxazole prophylaxis for 1-week post-RTX infusion effectively prevents post-RTX infectious complications, reduces infection-related mortality, and does not elevate the risk of serious AEs. However, it should be noted that this study was a single-center investigation without a placebo control. Trial registration The study was registered on the Chinese Clinical Trial Registry (trial registration identifier: ChiCTR2200063564).

Previous studies have shown that intravenous ceftriaxone or meropenem for 14 days, followed by oral trimethoprim–sulfamethoxazole for 1 year, cures 98% of people with Whipple's disease. However, intravenous therapy requires hospitalisation and carries risks for treatment-associated complications. The aim of this study was to investigate whether oral-only treatment for Whipple's disease is non-inferior to intravenous therapy. This phase 2/3, prospective, open-label, randomised, controlled, non-inferiority trial enrolled individuals aged 18 years or older with confirmed Whipple's disease from across Germany who had received treatment for less than 1 month at Charité–Universitätsmedizin Berlin. Participants were randomly assigned (1:1) with block randomisation to receive either intravenous ceftriaxone (2 g once per day) for 14 days, followed by oral trimethoprim–sulfamethoxazole (960 mg twice per day) for 12 months, or oral doxycycline (100 mg twice per day) plus hydroxychloroquine (200 mg twice per day) for 12 months. Ten participants who had already received intravenous ceftriaxone were non-randomly assigned to the intravenous treatment group. Participants in the oral-only treatment group were PCR-positive for Tropheryma whipplei in cerebrospinal fluid received trimethoprim–sulfamethoxazole (960 mg five times per day) until clearance. The primary outcome was complete clinical remission without recurrence during the observation period of 24 months, assessed in the intention-to-treat (ITT) population. The prespecified non-inferiority margin was –18%. Safety was a secondary endpoint, assessed in the ITT population. The study was registered with the EU Clinical Trials Register, EudraCT 2008–003951–54, and is completed. Between May 26, 2010, and Oct 30, 2018, we screened 310 individuals and enrolled 64 participants in the study. After exclusion of four individuals whose diagnosis was not confirmed, 31 participants were assigned to the intravenous treatment group and 29 to the oral-only treatment group. By ITT, 25 (81%) of 31 participants in the intravenous treatment group and 28 (97%) of 29 participants in the oral-only treatment group had complete clinical remission without recurrence. The risk difference was 15·9 percentage points (95% CI –1·2 to 33·1), with the lower bound of the 95% CI above our non-inferiority margin of –18%. A post-hoc per-protocol analysis confirmed the non-inferiority of oral-only treatment. No participant relapsed, but two participants in the intravenous treatment group died from nosocomial infections. Serious adverse events occurred in 13 (42%) of 31 participants in the intravenous treatment group and eight (28%) of 29 participants in the oral-only treatment group, but this difference was not statistically significant (p=0·244). Oral-only treatment of Whipple's disease was safe and non-inferior to sequential intravenous–oral treatment. Oral treatment facilitates patient management and might reduce hospital-acquired treatment complications and costs. German Research Foundation and the Robert Koch Institute. For the German translation of the abstract see Supplementary Materials section.

The antibiotic trimethoprim (TMP) is used to treat a variety of Escherichia coli infections, but its efficacy is limited by the rapid emergence of TMP-resistant bacteria. Previous laboratory evolution experiments have identified resistance-conferring mutations in the gene encoding the TMP target, bacterial dihydrofolate reductase (DHFR), in particular mutation L28R. Here, we show that 4’-desmethyltrimethoprim (4’-DTMP) inhibits both DHFR and its L28R variant, and selects against the emergence of TMP-resistant bacteria that carry the L28R mutation in laboratory experiments. Furthermore, antibiotic-sensitive E. coli populations acquire antibiotic resistance at a substantially slower rate when grown in the presence of 4’-DTMP than in the presence of TMP. We find that 4’-DTMP impedes evolution of resistance by selecting against resistant genotypes with the L28R mutation and diverting genetic trajectories to other resistance-conferring DHFR mutations with catalytic deficiencies. Our results demonstrate how a detailed characterization of resistance-conferring mutations in a target enzyme can help identify potential drugs against antibiotic-resistant bacteria, which may ultimately increase long-term efficacy of antimicrobial therapies by modulating evolutionary trajectories that lead to resistance. The efficacy of the antibiotic trimethoprim, which inhibits bacterial dihydrofolate reductase (DHFR), is limited by the rapid emergence of resistant bacteria. Here, Manna et al. show that 4’-desmethyltrimethoprim inhibits DHFR and a common TMP-resistant variant, and impedes evolution of antibiotic resistance by selecting against the emergence of this variant.