Evaluation of an Opt-Out Protocol for Antibiotic De-Escalation in Patients With Suspected Sepsis: A Multicenter, Randomized, Controlled Trial.

BACKGROUND: Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized, controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis. METHODS: We evaluated non-intensive care adults on broad-spectrum antibiotics despite negative blood cultures at 10 US hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs usual care. Primary outcome was post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If continued, clinicians discussed the rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided 2 measures: odds ratio of antibiotic continuation and ratio of mean DOT among those who continued antibiotics. RESULTS: Among 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs 84%; odds ratio, 0.68; 95% confidence interval [CI], .47-.98). DOT among those who continued antibiotics were similar (ratio of means, 1.06; 95% CI, .88-1.26). Fewer intervention patients were exposed to extended-spectrum antibiotics (36% vs 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar. CONCLUSIONS: An antibiotic opt-out protocol that targeted patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm. CLINICAL TRIALS REGISTRATION: NCT03517007.

A prospective study of extraesophageal reflux and potential microaspiration in patients hospitalized with COVID-19 in Jordan.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lung infection has represented a global challenge. Intriguingly, it has been shown that the alveolar lung epithelium expresses little Angiotensin Converting Enzyme receptor protein (ACE2), the entry receptor for SARS-CoV-2. Upper airway establishment of infection and translocation to the lung is well documented but other anatomical niches may be relevant to potentially serious lung infection. ACE2 is heavily expressed in the gastrointestinal tract and gastrointestinal symptoms support a clinical diagnosis of Coronavirus disease 2019 (COVID-19). This suggests a research question and the need to gather patient data exploring potential aerodigestive links in SARS-CoV-2 tranlocation and infection which may be relevant in the peripheral lung. This recognizes anatomical proximity and concepts of bi-directional movement between the Gastrointestinal and lung systems in normal physiology and disease. We have therefore explored the potential for gastro oesophageal reflux disease (GORD) micro aspiration and aeorodigestive pathophysiology in a novel prospective investigation of patients hospitalized with COVID-19. METHODS: This is a prospective descriptive cohort study of 210 patients who were hospitalized with a confirmed diagnosis of COVID-19. The cohort was divided into three groups of patients based on symptom severity and radiological results. The Reflux Symptom Index (RSI) was used to evaluate the presence and severity of GOR. An RSI greater than 13 is considered to be abnormal. Patients' saliva samples were tested using enzyme-linked immunosorbent assay (ELISA) to determine the level of salivary pepsin among the cohort of patients. RESULTS: A total of 210 patients with COVID-19 were enrolled in the study with 55.2% (116/210) classified as mildly ill, 31.9% (67/210) moderately ill and 12.9% (27/210) as severely ill. 34% (72/210) of the patients had an RSI score of over 13 and a median salivary pepsin value of 54 ± 29 ng/ml which suggested an incidence of extraesophageal reflux (EOR) in around a third of patients. The presence of respiratory comorbid conditions, an RSI score of over 13 and a salivary pepsin level of > 76ng/ml increased the risk of developing a more severe COVID-19 infection. CONCLUSION: The study showed a high prevalence of EOR among the study cohort and provide the first prospective evidence suggesting the potential for aerodigestive pathophysiology including microaspiration in COVID-19 disease. We believe that the results of our study support the need for more extensive research.

Randomised, double-blind, placebo-controlled pilot trial of omeprazole in idiopathic pulmonary fibrosis.

BACKGROUND: Cough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough. METHODS: Single-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency. RESULTS: Forty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole. CONCLUSIONS: A large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.

Does One Size Fit All With the Effects of Payment Reform? Dialysis Facility Payer Mix and Anemia Management Under the Expanded Medicare Prospective Payment System.

BACKGROUND: The effects of Medicare payment reforms aiming to improve the efficiency and quality of care by establishing greater financial accountability for providers may vary based on the extent and types of other coverage for their patient populations. Providers who are more resource constrained due to a less favorable payer mix face greater financial risks under such reforms. The impact of the expanded Medicare dialysis prospective payment system (PPS) on quality of care in independent dialysis facilities may vary based on the extent of higher payments from private insurers available for managing increased risks. OBJECTIVES: To evaluate whether anemia outcomes for dialysis patients in independent facilities differ under the Medicare PPS based on facility payer mix. DESIGN: We examined changes in anemia outcomes for 122,641 Medicare dialysis patients in 921 independent facilities during 2009-2014 among facilities with differing levels of employer insurance (EI). We performed similar analyses of facilities affiliated with large dialysis organizations, whose practices were not expected to change based on facility-specific payer mix. RESULTS: Among independent facilities, similar modeled trends in low hemoglobin for all 3 facility EI groups in 2009-2010 were followed by increased low hemoglobin during 2012-2014 for facilities with lower EI (P<0.01). Post-PPS standardized blood transfusion ratios were 9% higher for lower EI versus higher EI independent facilities (P<0.01). Among large dialysis organizations facilities, there was no divergence in low hemoglobin by payer mix under the PPS. CONCLUSIONS: There is evidence of poorer quality of care for anemia under the PPS in independent facilities with lower versus higher EI. Provider responses to payment reform may vary based on attributes such as payer mix that could have implications for health disparities.

Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients.

RATIONALE: Aspiration of infective subglottic secretions causes ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Mechanisms underlying subglottic colonization in critical illness have not been defined, limiting strategies for targeted prevention of VAP. OBJECTIVES: To characterize subglottic host defense dysfunction in mechanically ventilated patients in the ICU; to determine whether subglottic mucin contributes to neutrophil phagocytic impairment and bacterial growth. METHODS: Prospective subglottic sampling in mechanically ventilated patients (intubated for four or more days), and newly intubated control patients (intubated for less than 30 min); isolation and culture of primary subglottic epithelial cells from control patients; laboratory analysis of host innate immune defenses. MEASUREMENTS AND MAIN RESULTS: Twenty-four patients in the ICU and 27 newly intubated control patients were studied. Subglottic ICU samples had significantly reduced microbiological diversity and contained potential respiratory pathogens. The subglottic microenvironment in the ICU was characterized by neutrophilic inflammation, significantly increased proinflammatory cytokines and neutrophil proteases, and altered physical properties of subglottic secretions, including accumulation of mucins. Subglottic mucin from ICU patients impaired the capacity of neutrophils to phagocytose and kill bacteria. Phagocytic impairment was reversible on treatment with a mucolytic agent. Subglottic mucus promoted growth and invasion of bacterial pathogens in a novel air-liquid interface model of primary human subglottic epithelium. CONCLUSIONS: Mechanical ventilation in the ICU is characterized by substantial mucin secretion and neutrophilic inflammation. Mucin impairs neutrophil function and promotes bacterial growth. Mucolytic agents reverse mucin-mediated neutrophil dysfunction. Enhanced mucus disruption and removal has potential to augment preventive benefits of subglottic drainage.

Acceptability of alginate enriched bread and its effect on fat digestion in humans.

Lifestyle interventions and physical activity remain the cornerstone of obesity management, as pharmacological therapies (orlistat) are associated with gastrointestinal (GI) side effects. Combining orlistat with fibers can reduce side effects, improving compliance. Therefore, a fiber that inhibits lipase without side effects could help treat obesity. The aims of the present work were to assess whether alginate enriched bread could inhibit fat digestion, and assess the acceptability of alginate bread and its effect on GI wellbeing. A double-blind, randomised, controlled cross-over pilot study (NCT03350958) assessed the impact of an alginate bread meal on; lipid content in ileal effluent and circulating triacylglycerol levels. This was compared against the same meal with non-enriched (control) bread. GI wellbeing and acceptability of alginate bread was compared to control bread through daily wellbeing questionnaires and food diaries (NCT03477981). Control bread followed by alginate bread were consumed for two weeks respectively. Consumption of alginate bread reduced circulating triacylglycerol compared to control (2% reduction in AUC) and significantly increased lipid content in ileal effluent (3.8 g ±â€¯1.6 after 210 min). There were no significant changes to GI wellbeing when comparing alginate bread to control bread. A significant increase in the feeling of fullness occurred with alginate bread compared to baseline and the first week of control bread consumption. This study showed that sustained consumption of alginate enriched bread does not alter GI wellbeing and can decrease lipolysis, increasing lipid leaving the small intestine. Further studies are required to demonstrate that reduced fat digestion through the action of alginate can reduce fat mass or body weight.

Do Geographic Region, Medicaid Status, and Academic Affiliation Affect Access to Care Among Medicaid and Privately Insured Total Hip Arthroplasty Patients?

BACKGROUND: Medicaid provides health coverage to those beneath the federal poverty line. The literature shows that patients with Medicaid experience barriers to scheduling initial and follow-up visits, although this has not been studied in patients undergoing total hip arthroplasty (THA). The purpose of this study is to assess whether insurance type, geographic location, Medicaid expansion, or academic affiliation affect access to evaluation for THA. METHODS: The American Academy of Orthopedic Surgeons directory was used to call a total of 100 practices. Five random private and 5 random academic medical facilities were called from each of 5 Medicaid-expanded and 5 non-expanded states representing different US geographic regions. Calls were made by an investigator requesting the earliest available appointment for their fictitious parent to be evaluated for a THA. Half of the calls were made with the investigator reporting private insurance of Blue Cross Blue Shield (BCBS), and half reporting Medicaid. Appointment success rate and average time to appointment were compared. Further comparisons were drawn among Medicaid-expanded vs non-expanded states, geographic regions, and private vs academic affiliation. RESULTS: Appointments were successful for 99 of 100 (99%) calls made with BCBS, and 72 of 100 (72%) with Medicaid (P < .001). Success rates were significantly higher for BCBS, regardless of academic vs private affiliation. In all geographic regions, appointment success rate was significantly lower with Medicaid than with BCBS (P ≤ .01). Average time to appointment was also significantly longer for Medicaid (26 days) than private (13 days) insurance (P = .020). In the Medicaid group, appointment success rate was significantly greater for academically affiliated practices compared to private practices (84.0% vs 60.0%, respectively; P = .008). CONCLUSION: Patients with Medicaid seeking consultation for THA experience limits in access to evaluation for THA when compared to patients with private insurance, regardless of geographic region or affiliation of the practice.

Does Surgeon Fellowship Training Influence Outcomes in Hemiarthroplasty for Femoral Neck Fracture?

BACKGROUND: The aim of this study is to compare the outcomes (90 days and 1 year) of patients with femoral neck fracture undergoing hemiarthroplasty by surgeons with different fellowship training: trauma, arthroplasty, and general orthopedics. METHODS: This study is a retrospective review of consecutive patients undergoing hip hemiarthroplasty for femoral neck fracture from 2010 to 2018. Comorbidities, perioperative details, demographics, injury variables, and time-to-surgery were compared between the fellowship training cohorts, in addition to outcomes including dislocation, periprosthetic joint infection, and mortality at 90 days and 1 year. RESULTS: A total of 298 hips with an average age of 77.8 years underwent hemiarthroplasty for femoral neck fracture. Arthroplasty surgeons had a significantly shorter operative duration (82 minutes, P = .0014) and utilized the anterior approach more frequently (P < .0001). The general orthopedists had a significantly increased total surgical complication risk compared to both the arthroplasty and trauma fellowship-trained cohorts at both 90 days (11.8% vs 1.6% vs 3.9%, P = .015) and 1 year (18.2% vs 4.9% vs 7.1%, P = .008). The overall mortality risk was 11.7% at 90 days and 22.8% at 1 year. When adjusted for covariates, including comorbidities, gender, age, and preoperative walking capacity, both the arthroplasty fellowship-trained cohort (odds ratio 0.381, 95% confidence interval 0.159-0.912, P = .030) and the general orthopedist cohort (odds ratio 0.495; 95% confidence interval 0.258-0.952, P = .035) had reduced risk of 1-year mortality compared to the trauma fellowship-trained cohort. CONCLUSION: Hemiarthroplasty performed for femoral neck fractures may result in fewer complications when performed by arthroplasty fellowship-trained surgeons. An arthroplasty weekly on-call schedule and adjusted institutional protocols may be utilized to improve outcomes and reduce complications. LEVEL OF EVIDENCE: Level II, retrospective cohort.

Arteriovenous Fistula Maturation in Prevalent Hemodialysis Patients in the United States: A National Study.

BACKGROUND: Arteriovenous fistulas (AVFs) are the preferred form of hemodialysis vascular access, but maturation failures occur frequently, often resulting in prolonged catheter use. We sought to characterize AVF maturation in a national sample of prevalent hemodialysis patients in the United States. STUDY DESIGN: Nonconcurrent observational cohort study. SETTING & PARTICIPANTS: Prevalent hemodialysis patients having had at least 1 new AVF placed during 2013, as identified using Medicare claims data in the US Renal Data System. PREDICTORS: Demographics, geographic location, dialysis vintage, comorbid conditions. OUTCOMES: Successful maturation following placement defined by subsequent use identified using monthly CROWNWeb data. MEASUREMENTS: AVF maturation rates were compared across strata of predictors. Patients were followed up until the earliest evidence of death, AVF maturation, or the end of 2014. RESULTS: In the study period, 45,087 new AVFs were placed in 39,820 prevalent hemodialysis patients. No evidence of use was identified for 36.2% of AVFs. Only 54.7% of AVFs were used within 4 months of placement, with maturation rates varying considerably across end-stage renal disease (ESRD) networks. Older age was associated with lower AVF maturation rates. Female sex, black race, some comorbid conditions (cardiovascular disease, peripheral artery disease, diabetes, needing assistance, or institutionalized status), dialysis vintage longer than 1 year, and catheter or arteriovenous graft use at ESRD incidence were also associated with lower rates of successful AVF maturation. In contrast, hypertension and prior AVF placement at ESRD incidence were associated with higher rates of successful AVF maturation. LIMITATIONS: This study relies on administrative data, with monthly recording of access use. CONCLUSIONS: We identified numerous associations between AVF maturation and patient-level factors in a recent national sample of US hemodialysis patients. After accounting for these patient factors, we observed substantial differences in AVF maturation across some ESRD networks, indicating a need for additional study of the provider, practice, and regional factors that explain AVF maturation.

Unconventional T-cell recognition of an arthritogenic epitope of proteoglycan aggrecan released from degrading cartilage.

It has been proposed that peptide epitopes bind to MHC class II molecules to form distinct structural conformers of the same MHC II-peptide complex termed type A and type B, and that the two conformers of the same peptide-MHC II complex are recognized by distinct CD4 T cells, termed type A and type B T cells. Both types recognize short synthetic peptides but only type A recognize endosomally processed intact antigen. Type B T cells that recognize self peptides from exogenously degraded proteins have been shown to escape negative selection during thymic development and so have the potential to contribute to the pathogenesis of autoimmunity. We generated and characterized mouse CD4 T cells specific for an arthritogenic epitope of the candidate joint autoantigen proteoglycan aggrecan. Cloned T-cell hybridomas specific for a synthetic peptide containing the aggrecan epitope showed two distinct response patterns based on whether they could recognize processed intact aggrecan. Fine mapping demonstrated that both types of T-cell recognized the same core epitope. The results are consistent with the generation of aggrecan-specific type A and type B T cells. Type B T cells were activated by supernatants released from degrading cartilage, indicating the presence of antigenic extracellular peptides or fragments of aggrecan. Type B T cells could play a role in the pathogenesis of proteoglycan-induced arthritis in mice, a model for rheumatoid arthritis, by recognizing extracellular peptides or protein fragments of joint autoantigens released by inflamed cartilage.

Has dialysis payment reform led to initial racial disparities in anemia and mineral metabolism management?

Implementation of the Medicare ESRD prospective payment system (PPS) and changes to dosing guidelines for erythropoiesis-stimulating agents (ESAs) in 2011 appear to have influenced use of injectable medications among dialysis patients. Given historically higher ESA and vitamin D use among black patients, we assessed the effect of these policy changes on racial disparities in the management of anemia and mineral metabolism. Analyses used cross-sectional monthly cohorts for a period-prevalent sample of 7384 maintenance hemodialysis patients at 132 facilities from the Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor. Linear splines with knots at each policy change were used in survey-weighted regressions to estimate time trends in hemoglobin (Hgb), erythropoietin (EPO) dose, intravenous (IV) iron dose, ferritin, transferrin saturation (TSAT) concentration, parathyroid hormone (PTH), IV vitamin D dose, cinacalcet use, and phosphate binder use. From August 2010 to December 2011, mean Hgb declined from 11.5 to 11.0 g/dl (P<0.001), mean EPO dose declined from 20,506 to 14,777 U/wk (P<0.001), and mean serum PTH increased from 340 to 435 pg/ml (P<0.001). No meaningful differences by race were observed regarding the rates of change of management practices or laboratory measures (all P>0.21). Mean EPO and vitamin D dose and serum PTH levels remained higher in blacks. Despite evidence that anemia and mineral metabolism management practices have changed significantly over time, there was no immediate indication of racial disparities resulting from implementation of the PPS or ESA label change. Further studies are needed to examine effects among patient and facility subgroups.

Risk Adjustment and the Assessment of Disparities in Dialysis Mortality Outcomes.

Standardized mortality ratios (SMRs) reported by Medicare compare mortality at individual dialysis facilities with the national average, and are currently adjusted for race. However, whether the adjustment for race obscures or clarifies disparities in quality of care for minority groups is unknown. Cox model-based SMRs were computed with and without adjustment for patient race for 5920 facilities in the United States during 2010. The study population included virtually all patients treated with dialysis during this period. Without race adjustment, facilities with higher proportions of black patients had better survival outcomes; facilities with the highest percentage of black patients (top 10%) had overall mortality rates approximately 7% lower than expected. After adjusting for within-facility racial differences, facilities with higher proportions of black patients had poorer survival outcomes among black and non-black patients; facilities with the highest percentage of black patients (top 10%) had mortality rates approximately 6% worse than expected. In conclusion, accounting for within-facility racial differences in the computation of SMR helps to clarify disparities in quality of health care among patients with ESRD. The adjustment that accommodates within-facility comparisons is key, because it could also clarify relationships between patient characteristics and health care provider outcomes in other settings.

Biological activity of alginate and its effect on pancreatic lipase inhibition as a potential treatment for obesity.

Alginates are classed as a dietary fibre and have been shown to inhibit digestive enzymes in vitro, and therefore could be used as an obesity treatment. The current study aims to assess whether alginate in a bread vehicle maintains its inhibition properties despite cooking and digestion, and may therefore be used as a potential treatment for obesity. After 180 min in a model gut that replicates digestion in the mouth, stomach and small intestines alginate bread (AB), control bread (CB), CB with Manucol® DM alginate, free DM alginate and model gut solution were collected. DM, LFR 5/60 and SF200 were heated at 37 °C and 200 °C, with DM also heated at 50, 100 and 150 °C. Samples from the model gut and heated alginate were assessed for molecular size and inhibition properties using viscosity, gel filtration and a lipase turbidity assay. AB does not significantly increase viscosity in the model gut. Viscosity of alginate reduces beyond 100 °C, although alginate retains its inhibition properties up to 150 °C. Cooking into the bread does not reduce the molecular size of the alginate or affect its inhibition properties. These data demonstrate the robustness of alginates lipase inhibition despite the cooking process and digestion. Therefore adding alginate to a bread vehicle may have the potential in the treatment for obesity.

Evaluating the incidence of acute kidney injury and gentamicin synergy dosing for endocarditis.

Objectives: Current infective endocarditis guidelines recommend two different gentamicin synergy dosing strategies for selected Gram-positive organisms. The purpose of this analysis was to evaluate the incidence of acute kidney injury (AKI) with gentamicin synergy dosing, comparing divided-daily and once-daily dosing strategies for infective endocarditis (IE). Methods: Groups were split into patients who received gentamicin divided-daily dosing and once-daily (3 mg/kg) dosing for Gram-positive IE. The primary outcome was the incidence of AKI defined by RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria after starting gentamicin. A multivariable logistic regression analysis was performed to identify possible independent predictors of developing AKI. Notable secondary outcomes included hospital length of stay, need for gentamicin dose adjustments based on therapeutic drug monitoring, and assessment of each case of AKI using the Naranjo algorithm. Results: The incidence of AKI was significantly higher in the divided-daily group compared with the once-daily group (52.5% versus 13%, P < 0.01). The divided-dosing group had significantly longer median [IQR] hospital length of stay (19 days [12:29] versus 13.5 days [9:22], P < 0.01) and a greater number of patients who required dose adjustments (76.2% versus 21.7%, P < 0.01). The multivariable regression analysis showed that the divided-dosing strategy, duration and institution were independently associated with incidence of AKI. Conclusions: This analysis suggests a lower incidence of AKI in the treatment of endocarditis with gentamicin synergy dosed once-daily compared with a divided-daily dosing. Further studies are warranted to assess if there is a difference in efficacy between gentamicin synergy dosing strategies and in gentamicin compared with no gentamicin regimens for IE.

Evaluating Clinical Sequelae of the Carbapenem-Valproate Interaction: A Retrospective Analysis.

Background: Previous studies identified a rapid decrease in valproate serum concentrations when coadministered with a carbapenem; however, the specific consequences and subsequent therapy adjustments are not well described. We aimed to investigate the clinical and therapeutic implications of the carbapenem-valproate drug-drug interaction. Methods: This retrospective analysis included data from 2 large academic medical centers during January 2017 to June 2022. The primary outcome was incidence of seizures or behavioral events stratified by valproate indication. All adult patient encounters with concomitant administration of any carbapenem antimicrobial and valproate were included. Patients without prolonged exposure to valproate prior to hospitalization, without valproate levels pre- and post-carbapenem administration, with an admitting diagnosis of seizure, with exposure to other agents that decrease valproate concentrations, or who had a seizure during the hospitalization prior to carbapenem exposure were excluded. Results: Two hundred fifty-eight episodes of concomitant use among 78 unique adult patients were included. Valproate was used for seizure control in 41 patients (52.6%) and for mood-related disorders in 37 (47.4%). In those prescribed valproate for its antiepileptic properties, seizures occurred following carbapenem administration in 46.3% of encounters. In those taking valproate for mood-related disorders, 50.8% met the primary endpoint of behavioral disturbance. Conclusions: Our study demonstrates significant clinical implications of the carbapenem-valproate interaction. Clinicians should be aware of this interaction and consider alternative antimicrobial and/or antiepileptic agents whenever possible. Adding or increasing doses of antiepileptic agents and/or consultation with a neurologist prior to concomitant use should be considered when this combination cannot be avoided.