Differences In Clinical Response Research Articles

Novel insights into pathophysiology and therapeutic possibilities reveal further differences between AQP4-IgG- and MOG-IgG-associated diseases.

This review summarizes recent insights into the pathogenesis and therapeutic options for patients with MOG- or AQP4-antibodies. Although AQP4-IgG are linked to NMOSD, MOG-IgG-associated diseases (MOGAD) include a broader clinical spectrum of autoimmune diseases of the central nervous system (CNS). Details of membrane assembly of AQP4-IgG required for complement activation have been uncovered. Affinity-purified MOG-IgG from patients were shown to be pathogenic by induction of demyelination when the blood--brain barrier (BBB) was breached and by enhancement of activation of cognate T cells. A high-affinity AQP4-IgG, given peripherally, could induce NMOSD-like lesions in rats in the absence of BBB breach. Circulating AQP4-specific and MOG-specific B cells were identified and suggest differences in origin of MOG-antibodies or AQP4-antibodies. Patients with MOG-IgG show a dichotomy concerning circulating MOG-specific B cells; whether this is related to differences in clinical response of anti-CD20 therapy remains to be analyzed. Clinical trials of AQP4-IgG-positive NMOSD patients showed success with eculizumab (preventing cleavage of complement factor C5, thereby blocking formation of chemotactic C5a and membrane attack complex C9neo), inebilizumab (depleting CD19 + B cells), and satralizumab (anti-IL-6R blocking IL-6 actions). New insights into pathological mechanisms and therapeutic responses argue to consider NMOSD with AQP4-IgG and MOGAD as separate disease entities.

Modification of the association between paroxetine serum concentration and SERT-occupancy by ABCB1 (P-glycoprotein) polymorphisms in major depressive disorder

Selective serotonin reuptake inhibitors (SSRIs) exert substantial variability in effectiveness in patients with major depressive disorder (MDD), with up to 50-60% not achieving adequate response. Elucidating pharmacokinetic factors that explain this variability is important to increase treatment effectiveness. To examine potential modification of the relationship between paroxetine serum concentration (PSC) and serotonin transporter (SERT)-occupancy by single nucleotide polymorphisms (SNPs) of the ABCB1 gene, coding for the P-glycoprotein (P-gp) pump, in MDD patients. To investigate the relationship between ABCB1 SNPs and clinical response. Patients had MDD and received paroxetine 20 mg/day. We measured PSC after 6 weeks. We quantified SERT-occupancy with SPECT imaging (n = 38) and measured 17-item Hamilton Depression Rating Scale (HDRS17)-scores at baseline and after 6 weeks (n = 81). We genotyped ABCB1 at rs1045642 [3435C>T], rs1128503 [1236C>T], rs2032582 [2677G>T/A] and rs2235040 [2505G>A]. For our primary aim, we modeled mean SERT-occupancy in an Emax nonlinear regression model with PSC and assessed whether the model improved by genetic subgrouping. For our secondary aim, we used multivariate linear regression analysis. The rs1128503 and rs2032582 SNPs modified the relationship between PSC and SERT-occupancy in both our intention-to-treat and sensitivity analyses at the carriership level. However, we could not detect significant differences in clinical response between any of the genetic subgroups. Pharmacokinetic influences of the ABCB1 rs1128503 and rs2032582 represent a potentially relevant pharmacogenetic mechanism to consider when evaluating paroxetine efficacy. Future studies are needed to support the role of ABCB1 genotyping for individualizing SSRI pharmacotherapy.

DOP55 A real-world comparison of the effectiveness and safety of vedolizumab and anti-TNF therapies in early treatment initiation with first-line biologic therapy in ulcerative colitis: Results from EVOLVE

Abstract Background Evidence suggests that early treatment (Tx) with biologic agents in Crohn’s disease improves long-term clinical outcomes. However, there is less evidence in ulcerative colitis (UC), and data comparing early Tx with first-line biologic vedolizumab (VDZ) to anti-tumour necrosis factor (anti-TNF) in real-world settings is needed. This study compared the clinical effectiveness and safety of UC patients who initiated VDZ or an anti-TNF as a first-line biologic within 2 years following diagnosis. Methods This was a real-world, multi-country, retrospective chart review study in Canada, Greece and the United States where biologic-naïve UC patients (≥18 years old) were treated with VDZ or an anti-TNF (adalimumab, infliximab, golimumab) agent within 2 years following diagnosis (initiated Tx May 2014–March 2018). Clinical effectiveness and safety data were collected from Tx initiation to earliest of chart abstraction date, death, or 6 months post-Tx discontinuation (Canada only). Tx persistence was defined as the duration of time from treatment initiation to discontinuation. Analyses of cumulative rates of Tx persistence, clinical response, clinical remission and mucosal healing over 24 months were estimated using Kaplan–Meier analyses. Clinical response, remission and mucosal healing were assessed using pre-defined hierarchical algorithms of standard disease measures reported in the medical records. Analyses of incidence rates (per 100 person-years [PYs]) of disease exacerbations, disease-related surgeries, serious adverse events (SAEs) and serious infections (SIs) were performed. Adjusted analyses used inverse probability weighting to balance cohorts. Results This analysis included 176 UC patients (VDZ: 86; anti-TNF: 90) from 37 sites. Mean (SD) age at index date: VDZ, 41.4 (18.9); anti-TNF, 36.8 (15.6) years (p = 0.20) and the proportion male: VDZ, 58.1%; anti-TNF, 56.7% (p = 0.84). At 12 months, 72.9% and 58.1% continued VDZ and anti-TNF respectively (p = 0.03) (Figure 1A). Though there were no differences in clinical response, clinical remission or mucosal healing between VDZ and anti-TNF groups; VDZ patients were significantly less likely to experience disease exacerbations (HR = 0.47 [95% CI: 0.32–0.69]) and SAEs (HR = 0.37 [95% CI: 0.19–0.72]) (Figure 2). Adjusted outcomes (Figures 1C and D, and 2B) were similar to unadjusted outcomes. Conclusion EVOLVE is one of the first studies that compared early VDZ Tx to early anti-TNF Tx in biologic-naïve UC patients. Results showed VDZ was associated with higher persistence, lower likelihood of experiencing disease exacerbations and a more favourable safety profile. Thus, in early UC, Tx with VDZ may improve long-term clinical outcomes. Sample size limitations warrant further study.

Natural IgM dominates in vivo performance of liposomes

Prevalent deposition of plasma proteins on nano-surface alters the synthetic identity of liposomes in blood circulation. The key plasma protein(s) that can dominate in vivo fate of liposomes are of central importance for preclinical design and precise medication of liposome-based therapeutics. Herein, natural IgM, but not IgG, is identified to ubiquitously absorb on liposomal surface and takes the lead in complement activation of different species. The absorbed natural IgM, which negatively correlates with the in vivo performance of liposomes, becomes a potential indicator to guide the de novo design and optimization of liposomes. More importantly, the varying natural IgM levels in cancer patients may be one of the causal factors for clinical differences in response to liposome-based therapeutics. Clinical monitoring of the natural IgM level and its binding with liposomes becomes crucial to optimize the therapeutic regimen prior to the application of liposome-based therapeutics.

1483. Comparison of Outcomes in Urinary Tract Infections Caused by SPICE Organisms Treated with Non-Carbapenem-β-lactams vs. Non-β-lactams Agents

BackgroundThe “SPICE organisms” intrinsically produce low levels of a chromosomally encoded β-lactamase enzyme, AmpC. When SPICE organisms are exposed to certain antimicrobial agents, they can select for de-repressed mutants and induce the AmpC gene. No study to date has determined the optimal treatment of lower inoculum infections such as urinary tract infections (UTIs) caused by SPICE organisms.MethodsThis study is a single-center, retrospective observational review of adult hospitalized patients with a UTI caused by a SPICE organism from November 2012 to November 2015. The objective of this study was to compare outcomes amongst patients with UTIs caused by select SPICE organisms treated with drugs susceptible to AmpC hydrolysis (penicillins, cephalosporins except cefepime, and monobactams) vs. drugs stable against AmpC (carbapenems, cefepime, and non-β-lactam agents). The primary outcome was clinical response, defined as resolution of signs and symptoms of UTI without requiring escalation of antimicrobial therapy after 48 hours of therapy initiation. Secondary outcomes include 30-day infection-related readmission, 30-day infection recurrence rate, 30-day all-cause mortality, and length of hospital stay. Patients with resistance to ceftriaxone were reviewed for β-lactam exposure (≥7 days) within the last month.ResultsOne-hundred 56 patients were identified. Clinical response, 30-day infection-related readmission, 30-day infection recurrence, 30-day mortality rates, and median length of hospital stay were similar between the AmpC stable and AmpC susceptible groups (Table 1). Notably, 39.1% of patients with ceftriaxone resistance reported had recent β-lactam exposure vs. only 11.6% of patients without ceftriaxone resistance (P = 0.0028).ConclusionBased our data, there does not appear to be a difference in clinical response, 30-day-related readmission, 30-day infection recurrence, 30-day all-cause mortality rates, or length of stay in patients with UTIs treated with AmpC stable and AmpC susceptible agents. AmpC induction can be seen with at least 7 days of β-lactam use in the past 30 days as demonstrated by more frequent use of recent β-lactam agents in those with ceftriaxone resistance detected. Disclosures All authors: No reported disclosures.

Sex differences in adult zebrafish anxiolytic-like responses to diazepam and melatonin

Sex differences are an important variable in biomedical research. The zebrafish (Danio rerio) is rapidly becoming a critical novel model organism in translational neuroscience and neuropharmacology. Here, we examine the effects of sex on locomotor activity and anxiety-like behavior in adult zebrafish tested in the novel tank test following their exposure to two clinically relevant, common anxiolytic drugs diazepam and melatonin. While control female zebrafish were more active and anxious than males, both sexes showed anxiolytic responses to melatonin (0.232 mg/L) but only males responded to diazepam (16 μg/L). Revealing sex specificity in pharmacological responses, this study emphasizes the importance of sex differences in behavioral and pharmacological analyses in zebrafish. This may also be potentially relevant to modeling sex differences in clinical responses to anxiolytic drugs. Collectively, our data support sex differences in zebrafish behavioral responses and reinforce the growing utility of this aquatic model in CNS drug screening.

786 Efficacy of Vedolizumab in Older IBD Patients Based on Prior Biologic Exposure

INTRODUCTION: Evaluating the safety and efficacy of therapeutics for older patients with moderate to severe IBD is challenging as they are often excluded from clinical trials. Medication recommendations have primarily focused on risks of adverse effects, thus vedolizumab has emerged as the preferred first line therapy for these patients. However, there is a paucity of data regarding its clinical and endoscopic efficacy for the older population compared to other biologics. The aim of this study was to characterize the response rates and adverse effects to vedolizumab in older IBD patients based on prior medication and/or biologic exposure. METHODS: A retrospective cohort study of 55 consecutive older IBD patients, >60 years, treated at a tertiary care referral center from 1/2016 to 12/2018 with exposure to vedolizumab during the study period was performed. The primary outcome of interest was clinical response rates (defined as >50% improvement in abdominal pain and stool frequency) to vedolizumab induction in biologic-exposed vs biologic-naïve older patients. The secondary outcome was to compare adverse effects to vedolizumab in biologic-exposed vs biologic-naïve older patients within 1 year of initiation of therapy. RESULTS: Patients with prior biologic exposure were younger in age (69.1 ± 6.2 vs 74.6 ± 8.4 yrs, P = 0.01) and more likely to have also been treated with immunomodulators (76.2%) than naïve (30.8%) patients, P = 0.006. More bio-exposed patients had stricturing disease (60.0% vs 0%, P = 0.04) and were treated with combination therapy at induction (29.3% vs 0%, P = 0.05) compared to bio-naïve patients (Table 1). There were no differences in clinical response to induction (P = 0.76), vedolizumab dose escalation (P = 1.0), steroid use after induction (P = 0.36), and adverse effects (P = 1.0) between bio-exposed and naïve older patients (Figure 1). The addition of immunomodulators did not yield better outcomes for the older bio-exposed patients 50.0% combination therapy vs 55.2% monotherapy response rates, P = 1.0. CONCLUSION: These results suggest similar efficacy and safety of vedolizumab for older IBD patients regardless of prior biologic exposure based on clinical symptom assessment. Combination therapy did not add incremental benefit for this higher-risk age group or complications associated with additive immunosuppression. Further studies are needed to determine appropriate positioning of vedolizumab prior to or after anti-TNF agents or ustekinumab.

P045 Do Levels Matter? Maintaining Anti-TNF Class After Secondary Loss of Response to Adalimumab in Inflammatory Bowel Disease

BACKGROUND: Anti-tumor necrosis factor (Anti-TNF) biologic therapies have evolved as a mainstay of treatment for inflammatory bowel disease (IBD). However, 10%–20% of patients are primary non-responders to anti-TNF in clinical series and up to 40% of patients lose response to treatment over time. Current guidelines suggest that treatment failure in the setting of adequate drug concentrations are due to mechanistic failure and should be switched out of the anti-TNF class. Our aim was to assess the efficacy of switching to infliximab, rather than changing out of class, in patients with secondary loss of response to adalimumab who had a therapeutic drug level. METHODS: A retrospective chart review identified patients with ulcerative colitis (UC) and Crohn's disease (CD) treated with adalimumab within the University of North Carolina Inflammatory Bowel Disease clinic between January 1, 2007 and December 31, 2017. Patients with a therapeutic adalimumab level and treatment failure and who were subsequently treated with infliximab were included in the study. RESULTS: There were a total of 16 patients with therapeutic adalimumab levels (>5 μg/mL) and no antibody formation with treatment failure. In this population, 11 of the patients had CD, 3 patients had inflammatory bowel disease undifferentiated (IBDU) and 2 had UC. Ileocolonic CD (45.5%) and penetrating disease (54.4%) were the most common phenotypes. All patients had secondary loss of response to adalimumab and 87.5% had been increased to weekly dosing. Mean adalimumab level was 9.8 ± 6.8 μg/mL prior to switching to infliximab. Thirteen patients (81.3%) achieved clinical response with infliximab at 14 weeks and of the 8 patients with endoscopic assessments, 100% achieved endoscopic remission (5 with UC/IBDU and 3 with CD). There were a total of 6 patients in a sensitivity analysis assessing therapeutic levels >7 μg/mL. All patients were female, however all other characteristics in this group were similar to those patients evaluated with a therapeutic threshold of 5 μg/mL, including the rate of clinical response at 14 weeks (83.3%). When compared to 28 patients with adalimumab levels <5 μg/mL, there was no significant difference in clinical response at 14 weeks (P = 0.692). CONCLUSION(S): Switching within class to infliximab after secondary loss of response to adalimumab with a therapeutic level achieved clinical remission at 14 weeks in 81.3% of patients, and appears to be an acceptable strategy in selected patients. Therapeutic drug levels alone are not predictive of clinical response to a second anti-TNF.

Clinical Consequences of Antibody Formation, Serum Concentrations, and HLA-Cw6 Status in Psoriasis Patients on Ustekinumab.

Background:Ustekinumab for the treatment of psoriasis is currently administered in a standard dosing regimen. However, some patients tend to benefit from alternative dosing regimens, a step toward personalized medicine.Methods:To investigate the role of ustekinumab serum concentrations, anti-ustekinumab antibodies [AUA] and HLA-Cw6 status as tools for optimizing ustekinumab treatment, a multicenter prospective cohort study was conducted at an academic hospital with affiliated nonacademic hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2 and 3). Patients with plaque-type psoriasis were eligible if treated with ustekinumab for ≥16 weeks. Serum samples and Psoriasis Area and Severity Index scores were obtained at baseline, week 16, 28, 40, 52, and/or ≥64 of ustekinumab treatment.Results:A total of 137 patients with 229 observations for serum concentrations and AUA and 61 observations for HLA-Cw6 status were included. Presence of AUA (prevalence of 8.7%) was significantly associated with a diminished clinical response (P = 0.032). The median ustekinumab trough concentration was 0.3 mcg/mL (<0.02–3.80). No differences in serum concentrations were observed between moderate to good responders and nonresponders (P = 0.948). Serum trough concentrations were not affected by methotrexate comedication. Prevalence of HLA-Cw6 positivity was 41% with no statistically significant difference in clinical response between HLA-Cw6–positive and HLA-Cw6–negative patients (P = 0.164).Conclusions:The presence of AUA was associated with treatment failure in this patient population; measurement of AUA may therefore be a candidate marker for personalized pharmacotherapy. The clinical utility of ustekinumab serum trough concentrations or HLA-Cw6 status determination remains less clear. Further exploration on the potential of measuring ustekinumab serum concentrations and other biomarkers in predicting therapy outcomes should be encouraged.

Rituximab levels are associated with the B cell homeostasis but not with the clinical response in patients with rheumatoid arthritis.

ObjectiveTo study the levels of rituximab (RTX) and anti-RTX antibodies (ARAs) in patients with rheumatoid arthritis (RA) at 30, 90, and 180 days after the first infusion, in relation to clinical and serological parameters and B cell homeostasis.MethodsThirty-four patients with RA who failed to respond to anti-tumor necrosis factor therapy received RTX. At baseline, 4, 12, and 24 weeks after the first infusion of RTX, we performed a clinical assessment and determined the levels of RTX, ARAs, B cells, rheumatoid factors, anti-cyclic citrullinated peptide antibodies, immunoglobulins, and complements.ResultsRTX levels varied widely among patients. No ARAs were detected during the follow-up. Patients with lower levels of RTX presented with higher decreases in erythrocyte sedimentation rate, immunoglobulins, and complement 6 months after the first infusion. Patients with higher levels of RTX showed a higher B cell depletion at 90 days but an earlier B cell recovery than those with lower levels of RTX. No differences in clinical response were observed between the two groups at 6 months after starting the treatment.ConclusionOur findings suggest that RTX levels in the serum of patients with RA are related to B cell homeostasis and the severity of immunological parameters but not to the clinical response at 6 months.

Low-dose cyclosporine for active lupus nephritis: a dose titration approach.

Achievement of complete renal remission (CR) is an important goal in lupus nephritis (LN) treatment. The use of cyclosporine (CsA) for active LN has been challenged because of variations in CsA doses and reports of adverse reactions (AR). A cohort of 62 patients with active LN (induction-resistant LN and flared LN) who were treated with CsA was evaluated. CsA was started at 50 mg/day and titrated up 25 mg/day every 2-4 weeks until CR was achieved or until treatment termination because of AR. The range of CsA dosage was 50-200 mg/day, and mean CsA dose was 102.8 ± 50.43 mg/day (1.73 ± 0.91 mg/kg/day). CsA plus mycophenolate mofetil and prednisolone was administered to 35.5% of patients, while the other 64.5% were treated with CsA and prednisolone. 90.32% had achieved CR and 4.84% had partial remission after 12 months of treatment. UPCR (urinary protein:creatinine ratio) decreased significantly in both groups (2.58 ± 3.37 to 0.36 ± 0.71 and 2.32 ± 1.45 to 0.29 ± 0.24 respectively) (P < 0.001). Non-renal activity including arthritis, alopecia, hematologic and cutaneous conditions improved in all patients. Patients whose prednisolone dose were increase received higher doses of prednisolone at baseline than patients who had stable prednisolone dose, but after 12 months the difference in dosage was insignificant (p = 0.58). Patients with active LN can be effectively treated with low dose CsA, and the dose titration approach can lead to 90.32% CR with low AR rates. No difference in clinical response was observed among patients who received CsA plus prednisolone or CsA plus MMF and prednisolone.

Echinocandins vs. amphotericin B against invasive candidiasis in children and neonates: A meta-analysis of randomized controlled trials

The aim of this meta-analysis was to assess the efficacy and safety of treatment with echinocandins compared with amphotericin B in paediatric patients with invasive candidiasis. PubMed, Embase and Cochrane databases were searched up to August 2018. Only randomized controlled trials (RCTs) evaluating echinocandins and amphotericinB in the treatment of paediatric patients with invasive candidiasis were included. The outcomes were clinical responses and adverse effects. Five RCTs of 354 patients (191 patients in the echinocandins group and 163 patients in the amphotericin B group) were included in this study. Overall, no significant differences in clinical response were found between echinocandins and amphotericin B (odds ratio [OR], 1.38; 95% confidence interval [CI], 0.68-2.80; I2 = 39%). Similar results were also observed in the high-risk group (OR, 3.10; 95% CI, 0.10-97.23; I2 = 76%), the low-risk group (OR, 1.29; 95% CI, 0.36-4.62; I2 = 21%) and the neutropenia group (OR, 1.56; 95% CI, 0.75-3.26; I2 = 0%). The risk of discontinuing treatment because of adverse effects was significantly lower in the echinocandins group than in the amphotericin B group (OR, 0.30, 95% CI, 0.12-0.76; I2 = 0%). There were no differences in efficacy between the echinocandins group and the amphotericin B group in the treatment of invasive candidiasis in paediatric patients. However, the echinocandins group had a significantly lower risk of discontinuing treatment than the amphotericin B group.

Inhalation with intravenous loading dose of colistin in critically ill patients with pneumonia caused by carbapenem-resistant gram-negative bacteria.

Background:Despite the increasing use of colistin in clinical practice, the optimal dosing, and administration route have not been established. This study aimed to evaluate the clinical outcome and safety of intravenous (IV) colistin with a loading dose (LD) and adjunctive aerosolized (AS) colistin administration in critically ill patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) caused by carbapenem-resistant gram-negative bacteria (CRGNB).Methods:We retrospectively reviewed 191 critically ill patients who received colistin for the treatment of HAP or VAP caused by CRGNB. Patients were divided into three groups: non-LD IV (patients received only IV colistin without LD), LD IV (patients received only IV colistin with LD), and AS–LD (patients received IV colistin with LD and adjunctive AS colistin).Results:There was no difference in clinical response between the three groups. However, the rate of microbiological eradication was significantly higher in the AS–LD group (60%) than in the non-LD IV (31%), and LD IV (33%) groups (p = 0.010). Patients treated with adjunctive AS colistin in combination with LD IV had significantly lower 30-day mortality rates than patients treated with IV colistin alone (p = 0.027). After adjusting for potential confounding factors, adjunctive AS colistin was still significantly associated with lower mortality (adjusted OR 0.338, CI 95% 0.132–0.864, p = 0.024). However, nephrotoxicity did not change according to the use of LD regimen and AS colistin administration (p = 0.100).Conclusions:Adjunctive AS colistin in combination with IV colistin with LD was related to an improved 30-day mortality and microbiological outcome without an increase in nephrotoxicity in critically ill patients with HAP and VAP caused by CRGNB. The reviews of this paper are available via the supplemental material section.

Piperacillin-Tazobactam Versus Carbapenems for the Treatment of Nonbacteremic Urinary Tract Infections due to Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae.

Background: Carbapenems are the drug of choice for treatment of infections due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. Current evidence regarding piperacillin-tazobactam (PTZ) as an effective treatment alternative remains controversial. The purpose of this study was to determine the efficacy of PTZ versus carbapenems for treatment of nonbacteremic urinary tract infections (UTIs) due to ESBL-producing Enterobacteriaceae. Methods: A retrospective cohort study of patients treated for ESBL-related UTIs was conducted at three medical centers in the greater Middle Tennessee area. Patients were included if they were ≥ 18 years old, had a positive urine culture with an ESBL-producing organism, and received ≥ 48 hours of treatment with PTZ or carbapenem. Patients with bacteremia as well as those with isolates resistant to the treatment regimen selected were excluded. The primary objective was to determine the difference in clinical response between PTZ and carbapenem for treatment of ESBL-related UTIs. Clinical response was defined as absence of all of the following: (1) repeat admission for UTI caused by the same organism within 6 months, (2) repeat urine culture within 6 months showing growth of the same organism, or (3) a change in antimicrobial regimen due to subjective failure as determined by the ordering provider. Results: A total of 180 patients were included in the analysis (PTZ = 39; carbapenem = 141). There was no difference in clinical response between patients receiving PTZ and carbapenem (74.4% versus 80.9%; P = .38). Conclusion: PTZ may be an effective alternative to carbapenems for treatment of nonbacteremic UTIs due to ESBL-producing Enterobacteriaceae.

1484. Impact of Combination Vs. Monotherapy on Clinical Outcomes Associated with Stenotrophomonas maltophilia Pneumonia

Background Stenotrophomonas maltophilia is an emerging nosocomial pathogen with intrinsic resistance to several antibiotics, making it potentially challenging to treat. Studies have demonstrated treatment failures and resistance development with monotherapy (MT); however, limited clinical data have demonstrated improved outcomes with combination therapy (CT). The aim of this study was to compare clinical outcomes with CT vs. MT for S. maltophilia pneumonia.MethodsThis was a retrospective cohort study of patients admitted to OSUWMC between November 2011 and October 2017 with S. maltophilia pneumonia who received at least 48 hours of effective therapy. Data collected included baseline characteristics, APACHE II, immune status, and therapy received. The primary outcome was clinical response after seven days of effective therapy with CT vs. MT (i.e., improvement in signs and symptoms of infection, absence of fever for 24 hours, WBC normalization if immunocompetent, and negative blood cultures if concurrently bacteremic). Secondary outcomes included development of a nonsusceptible isolate; adverse drug events (ADEs); and 30-day microbiological cure, infection recurrence, and all-cause mortality. The Wilcoxon Rank-sum test, Pearson chi-squared test, and Fisher’s exact test were utilized as appropriate. A multivariable logistic regression model was used to assess clinical response while adjusting for confounding variables.ResultsThere were 252 patients with S. maltophilia pneumonia who met inclusion criteria, of which 38 received CT and 214 received MT. There was no difference in clinical response with CT vs. MT (47.4% vs. 39.7%, P = 0.38), even after controlling for immune status, APACHE II, and polymicrobial pulmonary infection (adjusted OR 1.49, 95% CI 0.62–3.60). Thirty-day microbiological cure (P = 0.44), recurrence (P = 0.53), all-cause mortality (P = 0.07), and isolation of a nonsusceptible isolate during (P = 0.96) or after (P = 0.85) therapy were also similar when comparing CT vs. MT. The most commonly reported ADEs were hyperkalemia and GI intolerance with trimethoprim/sulfamethoxazole and fluoroquinolones, respectively.ConclusionCT had similar efficacy and development of nonsusceptibility compared with MT for S. maltophilia pneumonia.Disclosures All authors: No reported disclosures.

Endobronchial brachytherapy in the management of lung malignancies: 20 years of experience in an Australian center

ObjectivesManagement of end-stage lung cancers focuses on symptom control, requiring multimodality management. Endobronchial brachytherapy (EBB) is an evidence-based approach allowing safe delivery of clinically meaningful radiation doses. We provide a summary of treatment characteristics and clinical outcomes of EBB in a single center. Methods and MaterialsOur retrospective study examined all EBB procedures performed at St George Hospital, NSW, Australia, between 1997 and 2016. Patients received single-fraction brachytherapy treatment under procedural sedation, using either the pulsed-dose-rate or high dose-rate modality. Symptomatic response was noted at the 4- to 6-week followup consultation. ResultsNinety-two EBB procedures were identified in 83 patients, with 75 patients treated with pulsed-dose-rate and 17 with high-dose-rate. Clinical and/or radiological airway obstruction in a prior high-dose irradiated volume was the most common indication for treatment (85%). Sixty (72%) patients had a partial or complete response of symptoms. Patients with hemoptysis were more likely to respond than those with airway obstruction (92% vs. 70%; p = 0.036). There was no difference in clinical response between pulsed-dose-rate and high-dose-rate patients (p = 0.24). Median overall survival was 8 months, with a statistically significant difference in those with clinical response (4 vs. 9 months; p = 0.0101). No Grade >2 toxicities were recorded. ConclusionsWe present the largest Australian series of EBB to date. We continue to demonstrate that despite a variety of symptomatic presentations and histologies, EBB is an effective approach to the palliation of malignant lung lesions. Given its low risk of toxicity, EBB is recommended as an option in the palliative treatment of endobronchial malignancies.

Efficacy and safety of ceftazidime/avibactam: a systematic review and meta-analysis.

Ceftazidime/avibactam is approved for complicated intra-abdominal and urinary tract infections (UTIs) based on results from randomized controlled trials (RCTs). Data regarding its effectiveness in treating hospital-acquired infections or resistant pathogens have not been systematically compiled. A systematic review and meta-analysis including RCTs evaluating ceftazidime/avibactam versus comparator for the treatment of any infection. Primary outcome was 30 day all-cause mortality. Subgroups of hospital-acquired infections and specific resistance phenotypes were planned. Seven publications (eight trials, 4093 patients) were included, reporting a baseline ∼25% of ESBL-carrying Enterobacteriaceae. No significant difference between ceftazidime/avibactam and comparator (mostly carbapenem) was demonstrated for 30 day all-cause mortality, late follow-up mortality and clinical response [relative risk (RR) 1.10, 95% CI 0.70-1.72, P = 0.69; RR 1.23, 95% CI 0.87-1.76, P = 0.25; RR 0.98, 95% CI 0.96-1.01, P = 0.21, respectively, without significant heterogeneity]. Higher microbiological response rate was demonstrated with ceftazidime/avibactam in patients with UTI (RR 1.14, 1.0-1.29, P = 0.05, I2 = 51%). No significant difference in clinical response was demonstrated for patients with ceftazidime-resistant pathogens (RR 1.02, 95% CI 0.94-1.10, P = 0.66, I2 = 0%). Results for other subgroups of resistant pathogens or hospital-acquired infection were not available. Serious adverse events (SAEs) were significantly more common with ceftazidime/avibactam (RR 1.24, 95% CI 1.00-1.54, P = 0.05, I2 = 0%). Ceftazidime/avibactam is clinically and microbiologically as effective as carbapenems for treatment of infections in a setting of ∼25% ESBL-carrying Enterobacteriaceae. Safety of the drug should be further evaluated owing to a higher rate of SAEs compared with carbapenems. Further studies should assess the drug's effectiveness in the treatment of carbapenemase-producing Enterobacteriaceae.

Human cytochrome P450 2B6 genetic variability in Botswana: a case of haplotype diversity and convergent phenotypes

Identification of inter-individual variability for drug metabolism through cytochrome P450 2B6 (CYP2B6) enzyme is important for understanding the differences in clinical responses to malaria and HIV. This study evaluates the distribution of CYP2B6 alleles, haplotypes and inferred metabolic phenotypes among subjects with different ethnicity in Botswana. A total of 570 subjects were analyzed for CYP2B6 polymorphisms at position 516 G > T (rs3745274), 785 A > G (rs2279343) and 983 T > C (rs28399499). Samples were collected in three districts of Botswana where the population belongs to Bantu (Serowe/Palapye and Chobe) and San-related (Ghanzi) ethnicity. The three districts showed different haplotype composition according to the ethnic background but similar metabolic inferred phenotypes, with 59.12%, 34.56%, 2.10% and 4.21% of the subjects having, respectively, an extensive, intermediate, slow and rapid metabolic profile. The results hint at the possibility of a convergent adaptation of detoxifying metabolic phenotypes despite a different haplotype structure due to the different genetic background. The main implication is that, while there is substantial homogeneity of metabolic inferred phenotypes among the country, the response to drugs metabolized via CYP2B6 could be individually associated to an increased risk of treatment failure and toxicity. These are important facts since Botswana is facing malaria elimination and a very high HIV prevalence.

Multidimensional endotypes of chronic rhinosinusitis and their association with treatment outcomes.

The expression of chronic rhinosinusitis (CRS) is multidimensional. Disease heterogeneity in patients with CRS remains poorly understood. This study aimed to identify endotypes of CRS using cluster analysis by integrating multidimensional characteristics and to explore their association with treatment outcomes. A total of 28 clinical variables and 39 mucosal cellular and molecular variables were analyzed using principal component analysis. Cluster analysis was performed on 246 prospectively recruited Chinese CRS patients with at least 1-year postoperative follow-up. Difficult-to-treat CRS was characterized in each generated cluster. Seven subject clusters were identified. Cluster 1 (13.01%) was comparable to the classic well-defined eosinophilic CRS with polyps, having severe disease and the highest proportion of difficult-to-treat CRS. Patients in cluster 2 (16.26%) and cluster 4 (13.82%) had relatively lower proportions of presence of polyps and presented mild inflammation with moderate proportions of difficult-to-treat cases. Subjects in cluster 2 were highly atopic. Cluster 3 (7.31%) and cluster 6 (21.14%) were characterized by severe or moderate neutrophilic inflammation, respectively, and with elevated levels of IL-8 and high proportions of difficult-to-treat CRS. Cluster 5 (4.07%) was a unique group characterized by the highest levels of IL-10 and lacked difficult-to-treat cases. Cluster 7 (24.39%) demonstrated the lowest symptom severity, a low proportion of difficult-to-treat CRS, and low inflammation load. Finally, we found that difficult-to-treat CRS was associated with distinct clinical features and biomarkers in the different clusters. Distinct clinicopathobiologic clusters of CRS display differences in clinical response to treatments and characteristics of difficult-to-treat CRS.

Pharmacological management of neuropathic pain in India: A consensus statement from Indian experts

Neuropathic pain (NeP) constitutes a major pain-related disorder, which is often underdiagnosed and undertreated. Adverse physical, psychological, and economic consequences associated with NeP lead to poor quality of life. Burden of NeP in developing countries like India is colossal. Various international guidelines provide effective approaches to diagnose and manage NeP. However, differences in the genetic makeup of Indian population can result in subtle differences in clinical response, considering their low body weight, drug metabolism ability, and pain perception. Similarly, treatment-related adverse effects may also vary. Practice of Indian physicians may also differ for choice of drugs based on their availability and affordability. In the absence of country-specific guidelines, this document could serve as a guiding tool for health-care providers, ensuring uniformity in the treatment of NeP. Thus, applicability of all recommendations from any of these guidelines in Indian setting demands careful evaluation. Clinical experience of Indian physicians suggests that there are lot many challenges (e.g., busy outpatient departments, nonavailability of screening questionnaires in regional languages, and availability and affordability of medications) faced by them when managing NeP. In addition, in India, there are no country-specific guidelines that would help them to address these challenges. The objective for this consensus was to develop an expert opinion guideline to harmonize the management of NeP in India. The expert panel consisted of experts from various specialties such as pain medicine, anesthesiology, diabetology, neurology, and orthopedics. The panel critically reviewed the existing literature evidence and guideline recommendations to provide India-specific consensus on the management of NeP. The final consensus document was reviewed and approved by all the experts. This expert opinion consensus will help health-care professionals as a guiding tool for effective management of NeP in India. Use of Douleur Neuropathique 4 (DN4) questionnaire for NeP screening should be routine in day-to-day clinical practice. For effective utilization of DN4 questionnaire, it should be converted to regional language. If DN4 questionnaire screening fails to identify NeP, it should not be disregarded and should not replace the sound clinical judgment from the treating physician. Diagnostic tests may be considered as a supplement to clinical judgment. Cost-effective treatment should be the initial choice. Dosing should be individualized based on efficacy and tolerability. Tricyclic antidepressants (TCAs), gabapentinoids, and serotonin-norepinephrine reuptake inhibitors (SNRIs) can be considered among initial choices. Tramadol can be considered as a second-line add-on treatment for NeP if there is partial response to the first-line agent either alone or in combination. Fixed-dose combination (FDC) of gabapentinoids such as pregabalin (75 mg) with TCA such as nortriptyline (10 mg) is synergistic and improves treatment adherence. Among other treatments, Vitamin B12 (methylcobalamin) can be used either alone or in combination for the management of NeP. Use of Vitamin D and steroids should be limited to specific NeP in individual cases. Referral to pain specialists can be considered if two drugs fail to provide relief in NeP.