Development of Predictive Models to Inform a Novel Risk Categorization Framework for Antibiotic Resistance in Escherichia coli-Caused Uncomplicated Urinary Tract Infection.

BACKGROUND: In clinical practice, challenges in identifying patients with uncomplicated urinary tract infections (uUTIs) at risk of antibiotic nonsusceptibility may lead to inappropriate prescribing and contribute to antibiotic resistance. We developed predictive models to quantify risk of nonsusceptibility to 4 commonly prescribed antibiotic classes for uUTI, identify predictors of nonsusceptibility to each class, and construct a corresponding risk categorization framework for nonsusceptibility. METHODS: Eligible females aged ≥12 years with Escherichia coli-caused uUTI were identified from Optum's de-identified Electronic Health Record dataset (1 October 2015-29 February 2020). Four predictive models were developed to predict nonsusceptibility to each antibiotic class and a risk categorization framework was developed to classify patients' isolates as low, moderate, and high risk of nonsusceptibility to each antibiotic class. RESULTS: Predictive models were developed among 87 487 patients. Key predictors of having a nonsusceptible isolate to ≥3 antibiotic classes included number of previous UTI episodes, prior ß-lactam nonsusceptibility, prior fluoroquinolone treatment, Census Bureau region, and race. The risk categorization framework classified 8.1%, 14.4%, 17.4%, and 6.3% of patients as having isolates at high risk of nonsusceptibility to nitrofurantoin, trimethoprim-sulfamethoxazole, ß-lactams, and fluoroquinolones, respectively. Across classes, the proportion of patients categorized as having high-risk isolates was 3- to 12-fold higher among patients with nonsusceptible isolates versus susceptible isolates. CONCLUSIONS: Our predictive models highlight factors that increase risk of nonsusceptibility to antibiotics for uUTIs, while the risk categorization framework contextualizes risk of nonsusceptibility to these treatments. Our findings provide valuable insight to clinicians treating uUTIs and may help inform empiric prescribing in this population.

Integrative omics analysis reveals insights into small colony variants of Staphylococcus aureus induced by sulfamethoxazole-trimethoprim.

BACKGROUND: Long-term treatment with trimethoprim-sulfamethoxazole (SXT) can lead to the formation of small-colony variants (SCVs) of Staphylococcus aureus. However, the mechanism behind SCVs formation remains poorly understood. In this study, we explored the phenotype and omics-based characterization of S. aureus SCVs induced by SXT and shed light on the potential causes of SCV formation. METHODS: Stable SCVs were obtained by continuously treating S. aureus isolates using 12/238 µg/ml of SXT, characterized by growth kinetics, antibiotic susceptibility testing, and auxotrophism test. Subsequently, a pair of representative strains (SCV and its parental strain) were selected for genomic, transcriptomic and metabolomic analysis. RESULTS: Three stable S. aureus SCVs were successfully screened and proven to be homologous to their corresponding parental strains. Phenotypic tests showed that all SCVs were non-classical mechanisms associated with impaired utilization of menadione, heme and thymine, and exhibited slower growth and higher antibiotic minimum inhibitory concentrations (MICs), compared to their corresponding parental strains. Genomic data revealed 15 missense mutations in 13 genes in the representative SCV, which were involved in adhesion, intramolecular phosphate transfer on ribose, transport pathways, and phage-encoded proteins. The combination analysis of transcriptome and metabolome identified 35 overlapping pathways possible associated with the phenotype switching of S. aureus. These pathways mainly included changes in metabolism, such as purine metabolism, pyruvate metabolism, amino acid metabolism, and ABC transporters, which could play a crucial role in promoting SCVs development by affecting nucleic acid synthesis and energy metabolism in bacteria. CONCLUSION: This study provides profound insights into the causes of S. aureus SCV formation induced by SXT. The findings may offer valuable clues for developing new strategies to combat S. aureus SCV infections.

Trimethoprim sulfamethoxazole prophylaxis and serious infections in granulomatosis with polyangiitis treated with rituximab.

OBJECTIVE: To assess the association of trimethoprim sulfamethoxazole (TMP-SMX) prophylaxis with serious infections in rituximab-treated patients with granulomatosis with polyangiitis (GPA). METHODS: This retrospective cohort study included adults with GPA (2011-2020) within the United States Merative™ Marketscan® Research Databases with ≥6 months enrolment prior to first (index) rituximab treatment. We defined TMP-SMX prophylaxis as a ≥28-day prescription dispensed after or overlapping the index date. Serious infection was a hospital primary diagnosis for infection (excluding viral or mycobacterial codes). Secondary outcomes were outpatient infection, PJP, and adverse events potentially attributable to TMP-SMX. Cox proportional hazards regression assessed the association of time-varying TMP-SMX with outcomes of interest, adjusting for potential confounders. Individuals were followed until the outcome of interest, end of database enrolment, or Dec 31, 2020. RESULTS: Among 919 rituximab-treated individuals (53% female), mean age was 52.1 years (SD 16) and 281 (31%) were dispensed TMP-SMX within 30 days of index date. Over a median of 496 (IQR 138, 979) days, 130 serious infections occurred among 104 individuals (incidence 6.1 [95% CI 5.0-7.4] per 100 person-years). Time-varying TMP-SMX was negatively associated with serious infection (adjusted HR 0.5; 95% CI 0.3-0.9). The aHR for outpatient infections was 0.8 (95% CI 0.6-1.1). The estimate for PJP was imprecise (13 events, unadjusted HR 0.2; 95% CI 0.03-1.8). TMP-SMX was potentially associated with adverse events (aHR 1.3; 95% CI 0.9-1.9). CONCLUSIONS: TMP-SMX prophylaxis was associated with reduced serious infections in rituximab-treated GPA, but may increase adverse events, warranting further study of optimal prophylaxis strategies.

Antibiotics efficacy in clinical and microbiological cure of uncomplicated urinary tract infection: a systematic review and network meta-analysis.

PURPOSE: Fosfomycin has been used more frequently in managing uncomplicated urinary tract infections (UTIs) due to decreased compliance and increased multidrug-resistant bacteria. The aim of this network meta-analysis was to assess the efficacy of Fosfomycin compared to Nitrofurantoin, Trimethoprim-Sulfamethoxazole (TMP-SMX), and Ciprofloxacin in terms of clinical and microbiological cure alongside with other measurements. MATERIALS AND METHODS: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). We included randomized control trials (RCTs) with uncomplicated UTI patients who received Fosfomycin, Nitrofurantoin, TMP-SMX, or Ciprofloxacin and reported the clinical or microbiological cure. We used Cochrane Risk of Bias Assessment Tool to assess the included studies' quality. R-software was used for all statistical analysis. We ranked all antibiotics using the netrank function which yielded P scores. Frequentist network meta-analysis was used to assess the efficacy of all outcomes. RESULTS: We included 13 RCTs with a total number of 3856 patients that showed Fosfomycin ranked the highest among the other antibiotics with respect to clinical cure (P-score = 0.99) and microbiological cure (P-score = 0.99) while Ciprofloxacin ranked the lowest (P-score = 0.11 and 0.02, respectively). Moreover, Ciprofloxacin yielded the highest relapse rate (P-score = 1), whereas TMP-SMX had the lowest relapse rate (P-score = 0.07). As for the adverse events, Ciprofloxacin demonstrated the highest adverse events as opposed to Fosfomycin (P-score = 0.98 and 0.05, respectively). CONCLUSION: The network meta-analysis demonstrated that Fosfomycin is the most effective antibiotic in treating uncomplicated UTIs with respect to clinical cure, microbiological cure, and adverse events profile.

Primary cutaneous nocardiosis of the ankle caused by N. brasiliensis: a case report.

Nocardia is a genus of aerobic, Gram-positive bacteria known for their filamentous and branching morphology. N. brasiliensis is the most common species causing cutaneous nocardiosis. We present a 67-year-old woman who developed abscesseson the back of her right ankle after walking barefoot on soil. Cultures from the cutaneous lesions grew N. brasiliensis. Antibiotic therapy with trimethoprim-sulfamethoxazole given for a month provided near-complete resolution of her lesions.

Relapsing bronchopneumonia due to community-associated methicillin-resistant Staphylococcus aureus: a case report.

BACKGROUND: The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has increased the incidence of community-onset MRSA infection. Respiratory tract infections caused by MRSA has been noted for their severity; however, repeated relapses that require extended antibiotic therapy are rare. CASE PRESENTATION: We report a case of relapsing bronchopneumonia caused by CA-MRSA in a 56-year-old man. The patient responded to antibiotics, but repeatedly relapsed after stopping treatment. MRSA was consistently isolated from airway specimens during each relapse. Extended oral antibiotic treatment with trimethoprim/sulfamethoxazole (TMP/SMX) for 6 months achieved infection control. Whole-genome sequencing of the isolated strain revealed that the causative agent was sequence type (ST)1/staphylococcal cassette chromosome mec (SCCmec) type IVa, a clone that is rapidly increasing in Japan. DISCUSSION AND CONCLUSIONS: This patient had an unusual course of MRSA bronchopneumonia with repeated relapses. Although the choice of antibiotics for long-term use in MRSA respiratory tract infections has not been well established, TMP/SMX was effective and well tolerated for long-term therapy in this case. The clinical course of infections related to the rapid emerging clone, ST1/SCCmec type IVa warrants further attention.

Synergistic Control of Trimethoprim and the Antimicrobial Resistome in Electrogenic Microbial Communities.

Synergistic control of the risks posed by emerging antimicrobials and antibiotic resistance genes (ARGs) is crucial for ensuring ecological safety. Although electrogenic respiration can enhance the biodegradation of several antimicrobials and reduce ARGs accumulation, the association mechanisms of antimicrobial biodegradation (trimethoprim, TMP) with the fate of the antimicrobial resistome remain unclear. Here, the biotransformation pathway of TMP, microbial associations, and functional gene profiles (e.g., degradation, antimicrobial resistance, and electron transfer) were analyzed. The results showed that the microbial electrogenic respiration significantly enhanced the biodegradation of TMP, especially with a cosubstrate sodium acetate supply. Electroactive bacteria enriched in the electrode biofilm positively correlated with potential TMP degraders dominated in the planktonic communities. These cross-niche microbial associations may contribute to the accelerated catabolism of TMP and extracellular electron transfer. Importantly, the evolution and dissemination of overall ARGs and mobile genetic elements (MGEs) were significantly weakened due to the enhanced cometabolic biodegradation of TMP. This study provides a promising strategy for the synergistic control of the water ecological risks of antimicrobials and their resistome, while also highlighting new insights into the association of antimicrobial biodegradation with the evolution of the resistome in an electrically integrated biological process.

A regimen based on the combination of trimethoprim/sulfamethoxazole with caspofungin and corticosteroids as a first-line therapy for patients with severe non-HIV-related pneumocystis jirovecii pneumonia: a retrospective study in a tertiary hospital.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening and severe disease in immunocompromised hosts. A synergistic regimen based on the combination of sulfamethoxazole-trimethoprim (SMX-TMP) with caspofungin and glucocorticosteroids (GCSs) may be a potential first-line therapy for PJP. Therefore, it is important to explore the efficacy and safety of this synergistic therapy for treating non-HIV-related PJP patients. METHODS: We retrospectively analysed the data of 38 patients with non-HIV-related PJP at the First Affiliated Hospital of Xi'an Jiaotong University. Patients were divided into two groups: the synergistic therapy group (ST group, n = 20) and the monotherapy group (MT group, n = 18). All patients were from the ICU and were diagnosed with severe PJP. In the ST group, all patients were treated with SMX-TMP (TMP 15-20 mg/kg per day) combined with caspofungin (70 mg as the loading dose and 50 mg/day as the maintenance dose) and a GCS (methylprednisolone 40-80 mg/day). Patients in the MT group were treated only with SMX-TMP (TMP 15-20 mg/kg per day). The clinical response, adverse events and mortality were compared between the two groups. RESULTS: The percentage of patients with a positive clinical response in the ST group was significantly greater than that in the MT group (100.00% vs. 66.70%, P = 0.005). The incidence of adverse events in the MT group was greater than that in the ST group (50.00% vs. 15.00%, P = 0.022). Furthermore, the dose of TMP and duration of fever in the ST group were markedly lower than those in the MT group (15.71 mg/kg/day vs. 18.35 mg/kg/day (P = 0.001) and 7.00 days vs. 11.50 days (P = 0.029), respectively). However, there were no significant differences in all-cause mortality or duration of hospital stay between the MT group and the ST group. CONCLUSIONS: Compared with SMZ/TMP monotherapy, synergistic therapy (SMZ-TMP combined with caspofungin and a GCS) for the treatment of non-HIV-related PJP can increase the clinical response rate, decrease the incidence of adverse events and shorten the duration of fever. These results indicate that synergistic therapy is effective and safe for treating severe non-HIV-related PJP.

Comparison of Doxycycline or Minocycline to Sulfamethoxazole-Trimethoprim for Treatment of Stenotrophomonas maltophilia Pneumonia.

BACKGROUND: Stenotrophomonas maltophilia is a multidrug-resistant organism with limited antibiotic treatment options. Minocycline and doxycycline may be appropriate, but clinical data are limited. OBJECTIVE: To compare tetracyclines (minocycline and doxycycline [TCN]) with standard of care, sulfamethoxazole-trimethoprim (TMP-SMZ), in S. maltophilia pneumonia treatment. METHODS: This retrospective, 2-center study evaluated patients treated for S. maltophilia pneumonia with TCN or TMP-SMZ for clinical success, defined as resolution of leukocytosis, fever, and tachypnea. Patients were classified as treatment with TCN or TMP-SMZ based on definitive agent used for ≥50% of the treatment course and ≥4 days. Inclusion criteria were age ≥18 years, S. maltophilia confirmed on respiratory culture from January 2013 to November 2020, and appropriate definitive antibiotic dosing. Pregnancy, incarceration, S. maltophilia-resistant or intermediate to definitive therapy, and combination therapy for treatment of S. maltophilia pneumonia were exclusion criteria. Secondary outcomes were microbiologic success and recurrence or reinfection within 30 days requiring treatment. RESULTS: A total of 80 patients were included (21 TCN [15 minocycline, 6 doxycycline], 59 TMP-SMZ). There was no difference in clinical success (28.6% vs 25.4%; P = 0.994), microbiologic success (n = 28, 55.6% vs 66.4%; P = 0.677), or recurrence or reinfection (n = 24, 66.7% vs 26.7%; P = 0.092) between TCN and TMP-SMZ, respectively. CONCLUSION AND RELEVANCE: Clinical and microbiologic success rates were similar in patients treated with TCN compared with TMP-SMZ for S. maltophilia pneumonia. These data suggest minocycline and doxycycline may be options to treat S. maltophilia pneumonia, but conclusive clinical data continue to be lacking.

Insights into the efficient mineralization of antibiotic trimethoprim in aqueous media by Fe2+ catalytically enhanced vacuum-UV irradiation: Kinetics, mechanisms, and toxicity evaluation.

The widespread existence of antibiotics in the environment has attracted growing concerns regarding the potential adverse effects on aquatic organisms, ecosystems, and human health even at low concentrations. Extensive efforts have been devoted to developing new methods for effective elimination of antibiotics from wastewater. Herein, a novel process of Fe2+ catalytically enhanced vacuum ultraviolet (VUV) irradiation was proposed as a promising approach for the removal of antibiotic trimethoprim (TMP) in water. Compared with UVC photolysis, VUV photolysis, and UVC/Fe2+, VUV/Fe2+ could increase the pseudo-first-order reaction rate constant of TMP removal by 6.6-38.4 times and the mineralization rate by 36.5%-59.9%. The excellent performance might originate from the synergistic effect of VUV and Fe2+, i.e., VUV irradiation could effectively split water and largely accelerate the Fe3+/Fe2+ cycle to generate more reactive oxygen species (ROS). EPR results indicated that •OH and O2•- were identified as the main ROS in the UVC/Fe2+ and VUV/Fe2+ processes, while •OH, O2•-, and 1O2 were involved in the VUV process. The operating parameters, such as Fe2+ dosage and initial TMP contents, were evaluated and optimized. Up to 8 aromatic intermediates derived from hydroxylation, demethylation, carbonylation, and methylene group cleavage were identified by UPLC-QTOF-MS/MS technique, the possible pathways of TMP degradation were proposed. Finally, the acute and chronic toxicity of intermediates formed during TMP degradation in the VUV/Fe2+ process were also evaluated.

Sulfamethoxazole-trimethoprim for pneumocystis pneumonia prophylaxis, causes of discontinuation and thrombocytopenia observed during administration: A single-center retrospective study.

INTRODUCTION: The development of pneumocystis pneumonia (PCP) has recently become a growing concern; thus, its prevention has become increasingly important. Sulfamethoxazole-trimethoprim (ST) is a cost-effective first-line and prophylactic treatment for PCP. However, ST administration criteria for PCP prophylaxis remain unclear and are often discontinued because of adverse events (AEs). In this study, we aimed to investigate the causes of ST discontinuation and the associated AEs using objective data. METHODS: We retrospectively analyzed the data of 162 patients admitted to Kansai Medical University Hospital between January 2018 and December 2020, who received ST for PCP prophylaxis. We compared clinical characteristics, laboratory data, and incidence of AEs between ST non-discontinuation and ST discontinuation groups. Additionally, we divided the patients into non-developing and developing thrombocytopenia (≥ Grade 1) groups based on the investigation results. RESULTS: No patients developed PCP while receiving ST. The most common causes of ST discontinuation were thrombocytopenia (37%), liver dysfunction (20%), and rash (18%). Multivariate analysis revealed thrombocytopenia (≥ Grade 1) as a factor significantly associated with ST discontinuation. Furthermore, we identified three factors correlated with thrombocytopenia (≥ Grade 1): age ≥50 years, lymphocyte count <1000/µL, and platelet count <180,000/µL. CONCLUSIONS: Patients with the aforementioned factors are at higher risk of developing thrombocytopenia (≥ Grade 1) during ST administration for PCP prophylaxis. Therefore, platelet count monitoring is essential to enhance safety and efficacy of ST treatment. Nonetheless, further research is warranted to explore additional implications and interventions.

Successful maintenance treatment of disseminated nocardiosis with cerebral abscess in a severely immunocompromised patient allergic to trimethoprim-sulfamethoxazole using moxifloxacin and high-dose minocycline: A case report.

Nocardiosis in patients after allogeneic hematopoietic stem cell transplantation (HSCT) is rare, but is associated with a significant mortality risk. Although trimethoprim-sulfamethoxazole (TMP/SMX) remains the cornerstone of nocardiosis treatment, optimal alternative therapies for patients intolerant to TMP/SMX are not well-established. Herein, we report a case of disseminated nocardiosis with bacteremia and multiple lesions in the lungs and brain caused by Nocardia farcinica, in a 60-year-old man who had previously undergone allogeneic HSCT and was receiving immunosuppressants for severe chronic graft-versus-host disease. The patient received atovaquone for the prophylaxis of Pneumocystis pneumonia because of a previous serious allergic reaction to TMP/SMX. The patient was initially treated with imipenem/cilastatin and amikacin, which were later switched to ceftriaxone and amikacin based on the results of antimicrobial susceptibility testing. After switching to oral levofloxacin and a standard dose of minocycline, the patient experienced a single recurrence of brain abscesses. However, after switching to oral moxifloxacin and high-dose minocycline, the patient did not experience any relapses during the subsequent two years and seven months of treatment. In treating nocardiosis with brain abscesses, it is crucial to select oral antibiotics based on the antimicrobial susceptibility test results and pharmacokinetics, especially when TMP/SMX is contraindicated. A combination of oral moxifloxacin and high-dose minocycline could be a promising alternative therapy.

Development and validation of method for the simultaneous determination of sulfamethazine, trimethoprim and doxycycline in veterinary formulation using high performance liquid chromatography.

Sulfamethazine (SMZ), trimethoprim (TMP) and doxycycline (DOXY) are drugs of choice used in the treatment of intestinal and respiratory infections that affect poultry and swine. The aim of this study was develop and validate a simple, sensitive and fast method for the simultaneous determination of SMZ, TMP and DOXY in veterinary formulations by high-performance liquid chromatography. The separation was performed on a Macherey-Nagel C8 analytical column (4 × 125 mm, 5 µm), with a flow rate of 0.5 ml min-1 and detection at 268, 270 and 350 nm, for SMZ, TMP and DOXY, respectively. All measurements were performed in acetonitrile-water (45:55 v/v; pH 3.0). The analytical curves were linear (r > 0.9997) in the concentration range of 5.0-35.0 µg ml-1 for SMZ, 1.0-7.0 µg ml-1 for TMP and 7.0-13.0 µg ml-1 for DOXY. The method proved to be precise, robust, accurate and selective. In accelerated stability, the sample was analyzed for 6 months, with no major variations observed in organoleptic analysis and pH. Therefore, the developed method was proved to be suitable for routine quality control analyses for the simultaneous determination of SMZ, TMP and DOXY in pharmaceutical formulations.

The effect of salinity on trimethoprim adsorption by activated sludge extracellular polymeric substances at trace concentration.

The saline wastewater produced in industrial activities and seawater use would flow into wastewater treatment plants and affect the characteristic of extracellular polymeric substance (EPS) of activated sludge, which could potentially impact the removal of antibiotics via adsorption. Nonetheless, the effect of salinity on trimethoprim adsorption by activated sludge extracellular polymeric substances at trace concentration and the underlying mechanism remain largely unknown. In this study, the effect of salinity on the adsorption removal of a typical antibiotic, i.e., trimethoprim (TMP) at trace concentration (25.0 µg/L) was evaluated. The results showed the content of EPS was decreased significantly from 56.36 to 21.70 mg/g VSS when the salinity was increased from 0 to 10 g/L. Protein fractions occupied the predominant component of EPS, whose concentration was decreased from 38.17 to 12.83 mg/g VSS. The equilibrium adsorption capacity of activated sludge for TMP was decreased by 49.70% (from 4.97 to 2.50 µg/g VSS). The fluorescence quenching results indicated the fluorescence intensity of tryptophan-like substances was decreased by 30% and the adsorption sites of EPS were decreased from 0.51 to 0.21 when the salinity was increased. The infrared spectrum and XPS results showed that the nitrogen-containing groups from protein were decreased significantly. The circular dichroic analysis showed α helix structure of protein in EPS was decreased with the increase of salinity, which was responsible for the decrease of adsorption capacity for TMP.

Heterogeneous activation of self-generated H2O2 by Pd@UiO-66(Zr) for trimethoprim degradation: Efficiency and mechanism.

The Fenton reaction is recognized as an effective technique for degrading persistent organic pollutants, such as the emerging pollutant trimethoprim (TMP). Recently, due to the excellent reducibility of active hydrogen ([H]), Pd-H2 has been preferred for Fenton-like reactions and the specific H2 activation of Pd-based catalysts. Herein, a heterogeneous Fenton catalyst named the hydrogen-accelerated oxygen reduction Fenton (MHORF@UiO-66(Zr)) system was prepared through the strategy of building ships in the bottle. The [H] has been used for the acceleration of the reduction of Fe(III) and self-generate H2O2. The systematic characterization demonstrated that the nano Pd0 particle was highly dispersed into the UiO-66(Zr). The results found that 20 mg L-1 of TMP was thoroughly degraded within 90 min in the MHORF@UiO-66(Zr) system under conditions of initial pH 3, 30 mL min-1 H2, 2 g L-1 Pd@UiO-66(Zr) and 25 µM Fe2+. The hydroxyl radical as well as the singlet oxygen were evidenced to be the main reactive oxygen species by scavenging experiments and electron spin resonance. In addition, both reducing Fe(III) and self-generating H2O2 could be achieved due to the strong metal-support interaction (SMSI) between the nano Pd0 particles and UiO-66(Zr) confirmed by the correlation results of XPS and calculation of density functional theory. Finally, the working mechanism of the MHORF@UiO-66(Zr) system and the possible degradation pathway of the TMP have been proposed. The novel system exhibited excellent reusability and stability after six cyclic reaction processes.

Risk factors for adverse drug reactions to sulfamethoxazole-trimethoprim prophylaxis in patients with rheumatic and musculoskeletal diseases.

OBJECTIVES: Risk factors for adverse drug reactions (ADRs) associated with prophylactic sulfamethoxazole-trimethoprim (SMX/TMP) in patients with rheumatic and musculoskeletal diseases undergoing immunosuppressive therapy remain unclear, we aimed to identify the risk factors associated with ADRs. METHODS: Consecutive patients with rheumatic and musculoskeletal diseases, who were admitted to Keio University Hospital and received prophylactic administration of SMX/TMP, were included. Data regarding ADRs to SMX/TMP were collected to identify associated risk factors using multivariable analysis. RESULTS: Of 438 patients included in the analysis, 82 (18.7%) experienced ADRs. Patients in the ADRs group were significantly older, had chronic kidney disease, and exhibited lower lymphocyte and platelet counts, lower albumin levels, lower estimated glomerular filtration rates, higher aspartate aminotransferase levels, and higher ferritin levels than those in the non-ADR group. Regarding underlying rheumatic and musculoskeletal diseases, adult-onset Still's disease (ASD) was associated with a significantly higher incidence of ADRs (67%) than other diseases. Multivariable analysis identified the presence of ASD and low lymphocyte counts as independent risk factors for allergic ADRs, and older age and use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers for non-allergic ADRs. CONCLUSIONS: Risk factors for ADRs associated with prophylactic SMX/TMP treatment in patients with rheumatic and musculoskeletal diseases were identified.

Antibiotic Myths for the Infectious Diseases Clinician.

Antimicrobials are commonly prescribed and often misunderstood. With more than 50% of hospitalized patients receiving an antimicrobial agent at any point in time, judicious and optimal use of these drugs is paramount to advancing patient care. This narrative will focus on myths relevant to nuanced consultation from infectious diseases specialists, particularly surrounding specific considerations for a variety of antibiotics.

Treatment With Reduced-Dose Trimethoprim-Sulfamethoxazole Is Effective in Mild to Moderate Pneumocystis jirovecii Pneumonia in Patients With Hematologic Malignancies.

BACKGROUND: Recent studies have reported that reduced-dose trimethoprim-sulfamethoxazole (TMP-SMX) may be effective in the treatment of Pneumocystis jirovecii pneumonia (PJP), but data are lacking for patients with hematologic malignancies. METHODS: This retrospective study included all adult hematologic patients with PJP between 2013 and 2017 at 6 Swedish university hospitals. Treatment with 7.5-15 mg TMP/kg/day (reduced dose) was compared with >15-20 mg TMP/kg/day (standard dose), after correction for renal function. The primary outcome was the change in respiratory function (Δpartial pressure of oxygen [PaO2]/fraction of inspired oxygen [FiO2]) between baseline and day 8. Secondary outcomes were clinical failure and/or death at day 8 and death at day 30. RESULTS: Of a total of 113 included patients, 80 patients received reduced dose and 33 patients received standard dose. The overall 30-day mortality in the whole cohort was 14%. There were no clinically relevant differences in ΔPaO2/FiO2 at day 8 between the treatment groups, either before or after controlling for potential confounders in an adjusted regression model (-13.6 mm Hg [95% confidence interval {CI}, -56.7 to 29.5 mm Hg] and -9.4 mm Hg [95% CI, -50.5 to 31.7 mm Hg], respectively). Clinical failure and/or death at day 8 and 30-day mortality did not differ significantly between the groups (18% vs 21% and 14% vs 15%, respectively). Among patients with mild to moderate pneumonia, defined as PaO2/FiO2 >200 mm Hg, all 44 patients receiving the reduced dose were alive at day 30. CONCLUSIONS: In this cohort of 113 patients with hematologic malignancies, reduced-dose TMP-SMX was effective and safe for treating mild to moderate PJP.

Revisiting the Evidence Base for Modern-Day Practice of the Treatment of Toxoplasmic Encephalitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Toxoplasmic encephalitis (TE) is an opportunistic infection of people with human immunodeficiency virus (HIV) or other causes of immunosuppression. Guideline-recommended treatments for TE are pyrimethamine and sulfadiazine (P-S) or pyrimethamine and clindamycin (P-C); however, a substantial price increase has limited access to pyrimethamine. Consequently, some centers have transitioned to trimethoprim-sulfamethoxazole (TMP-SMX), an inexpensive alternative treatment. We aimed to review the evidence on the efficacy and safety of pyrimethamine-containing therapies vs TMP-SMX. METHODS: We searched for and included randomized controlled trials (RCTs) and observational studies of TE treatments, regardless of HIV status. Data for each therapy were pooled by meta-analysis to assess the proportions of patients who experienced clinical and radiologic responses to treatment, all-cause mortality, and discontinuation due to toxicity. Sensitivity analyses limited to RCTs directly compared therapies. RESULTS: We identified 6 RCTs/dose-escalation studies and 26 single-arm/observational studies. Identified studies included only persons with HIV, and most predated modern antiretroviral treatment. Pooled proportions of clinical and radiologic response and mortality were not significantly different between TMP-SMX and pyrimethamine-containing regimens (P > .05). Treatment discontinuation due to toxicity was significantly lower in TMP-SMX (7.3%; 95% confidence interval [CI], 4.7-11.4; I2 = 0.0%) vs P-S (30.5%; 95% CI, 27.1-34.2; I2 = 0.0%; P < .01) or P-C (13.7%; 95% CI, 9.8-18.8; I2 = 32.0%; P = .031). These results were consistent in analyses restricted to RCT data. CONCLUSIONS: TMP-SMX appears to be as effective and safer than pyrimethamine-containing regimens for TE. These findings support modern RCTs comparing TMP-SMX to pyrimethamine-based therapies and a revisiting of the guidelines.

Manifestations and Management of Trimethoprim/Sulfamethoxazole-Resistant Nocardia otitidiscaviarum Infection.

Nocardia can cause systemic infections with varying manifestations. Resistance patterns vary by species. We describe N. otitidiscavarium infection with pulmonary and cutaneous manifestations in a man in the United States. He received multidrug treatment that included trimethoprim/sulfamethoxazole but died. Our case highlights the need to treat with combination therapy until drug susceptibilities are known.