Mixed-methods feasibility study to inform a randomised controlled trial of proton pump inhibitors to reduce strictures following neonatal surgery for oesophageal atresia.

OBJECTIVES: This mixed-methods feasibility study aimed to explore parents' and medical practitioners' views on the acceptability and design of a clinical trial to determine whether routine prophylactic proton pump inhibitors (PPI) reduce the incidence of anastomotic stricture in infants with oesophageal atresia (OA). DESIGN: Semi-structured interviews with UK parents of an infant with OA and an online survey, telephone interviews and focus groups with clinicians. Data were analysed using reflexive thematic analysis and descriptive statistics. PARTICIPANTS AND SETTING: We interviewed 18 parents of infants with OA. Fifty-one clinicians (49 surgeons, 2 neonatologists) from 20/25 (80%) units involved in OA repair completed an online survey and 10 took part in 1 of 2 focus groups. Interviews were conducted with two clinicians whose survey responses indicated they had concerns about the trial. OUTCOME MEASURES: Parents and clinicians ranked the same top four outcomes ('Severity of anastomotic stricture', 'Incidence of anastomotic stricture', 'Need for treatment of reflux' and 'Presence of symptoms of reflux') as important to measure for the proposed trial. RESULTS: All parents and most clinicians found the use, dose and duration of omeprazole as the intervention medication, and the placebo control, as acceptable. Parents stated they would hypothetically consent to their child's participation in the trial. Concerns of a few parents and clinicians about infants suffering with symptomatic reflux, and the impact of this for study retention, appeared to be alleviated through the symptomatic reflux treatment pathway. Hesitant clinician views appeared to change through discussion of parental support for the study and by highlighting existing research that questions current practice of PPI treatment. CONCLUSIONS: Our findings indicate that parents and most clinicians view the proposed Treating Oesophageal Atresia with prophylactic proton pump inhibitors to prevent STricture (TOAST) trial to be feasible and acceptable so long as infants can be given PPI if clinicians deem it clinically necessary. This insight into parent and clinician views and concerns will inform pilot phase trial monitoring, staff training and the development of the trial protocol.

Evaluación de la interacción de capecitabina con inhibidores de la bomba de protones en pacientes con cáncer de colon metastásico / Evaluation of the interaction of capecitabin with proton pump inhibitors in patients with metastatic colon cáncer

Objetivo: Evaluar el impacto clínico que la interacción de capecitabina con inhibidores de la bomba de protones (IBP) puede tener sobre la efectividad del tratamiento de mantenimiento en pacientes con cáncer de colon metastásico (CCm). Material y métodos: Estudio retrospectivo, observacional descriptivo que incluyó a todos los pacientes con CCm tratados con capecitabina sola o en combinación entre enero 2013-diciembre 2016. Los pacientes fueron divididos en dos grupos según si fueron o no tratados con IBP concomitantemente con capecitabina. Se evaluaron variables demográficas, farmacológicas y clínicas, siendo la supervivencia libre de progresión (SLP) la variable elegida para evaluar el impacto clínico de la interacción. Resultados: Se incluyeron 150 pacientes. De ellos, el 57,33% varones, media de edad 70,10±12,06 años; el 55,33% tuvieron un ECOG 1 y el 58,67% utilizaron IBP. Un 39,33% fueron tratados con capecitabina en monoterapia, 31,33% CapeOx, y 20% capecitabina+bevacizumab y 9,33% CapeOx+bevacizumab. El 53,33% tuvo un tratamiento basado en capecitabina en primera línea, la frecuencia de variaciones de tratamiento fue de 42,0% reducción de dosis, 38,0% retraso, y 12% interrupción tratamiento. El 78,0% presentó alguna toxicidad, destacando 34,67% diarrea y 30,0% (síndrome mano-pie). La SLP media fue de 6,69 vs 6,0 meses (HR=0,97; IC95% 0,68-1,39; p=0,87) en favor de los pacientes que no utilizaron IBP, aunque la relación fue no significativa. Conclusiones: En la población estudiada, los pacientes con CCm que recibieron tratamiento de mantenimiento basado en capecitabina y que utilizaron IBP simultáneamente, presentaron una tendencia no significativa a la disminución de la SLP. (AU)

Objective: To evaluate the clinical impact that the interaction of capecitabine with proton pump inhibitors (PPIs) may have on the effectiveness of maintenance treatment in patients with metastatic colon cancer (mCC). Material and methods: Retrospective, observational, descriptive study that included all patients with CCm treated with capecitabine alone or in combination between January 2013-December 2016. The patients were divided into two groups according to whether or not they were treated with PPIs concomitantly with capecitabine. Demographic, pharmacological and clinical variables were evaluated, with progression free survival (PFS) being the variable chosen to evaluate the clinical impact of interaction. Results:150 patients were included. Of them, 57.33% were men, mean age 70.10±12.06 years; 55.33% had an ECOG 1 and 58.67% used it in PPIs. 39.33% were treated with capecitabine in monotherapy, 31.33% CapeOx, and 20% capecitabine+bevacizumab and 9.33% CapeOx+bevacizumab. 53.33% had a first-line capecitabine-based treatment, the frequency of treatment variations was 42.0% dose reduction, 38.0% delay, and 12% treatment interruption. 78.0% presented any toxicity, (highlighting 34.67% diarrhea and 30.0% hand-foot syndrome). The mean PFS was 6.69 vs 6.0 months (HR=0.97; 95% CI 0.68-1.39; p=0.87) in favor of patients who did not use IBP, although the relationship was not significant. Conclusions: In the population studied, patients with mCC who received maintenance treatment based on capecitabine and who used PPIs simultaneously, showed a non-significant trend towards a decrease in PFS. (AU)

Controlled release floating drug delivery system for proton pump inhibitors lansoprazole: In-vitro, In-vivo floating and pharmacokinetic evaluation.

Lansoprazole (LPZ) show poor bioavailability because of first pass effect and absorption factors. The floating delivery systems could reduce fluctuations in plasma drug concentration through maintaining desirable plasma drug concentration. The objective of present study was to enhance bioavailability despite first pass effect through continuous availability of drug from floating system. Gum tragacanth (GT) and itaconic acid (IA) based floating hydrogels (FH) were synthesized. Parameters optimized were; microwave radiation exposure time, pH, GT:IA ratio and concentration of the glutaraldehyde. Optimized FH were evaluated for entrapment efficiency (% EE), in-vitro release, FTIR, SEM, and in- vitro and in-vivo floating study. Finally, pharmacokinetic was evaluated in ulcer-induced SD rats. Grafting percentage, swelling ratio and %EE of LPZ was 115%, Ì´250% and 90%, respectively. Microwave radiation exposure time, pH of reaction medium, GT:IA ratios and cross linker concentration were 2 min, pH 5, ratios 2:1 and 0.02%, respectively. The optimized FH showed acceptable floating behavior. The X-ray images revealed that hydrogels remained floated over gastric contents up to 24 hours. The in-vitro release and pharmacokinetics revealed availability of LPZ upto to 24h in-vitro and in ulcer-induced SD rats, respectively. The present hydrogels based floating system of lansoprazole is capable to extend the gastric residence time upto 24 hours.

Tratamiento con inhibidores de la bomba de protones. ¿Realmente lo necesita el paciente? / Proton-pump inhibitors treatment. Does your patient really need it?

Introducción: Los inhibidores de la bomba de protones (IBP) son fármacos utilizados frecuentemente para el manejo de diferentes enfermedades gastrointestinales. Aunque sus indicaciones y dosis están bien establecidas, se han comunicado elevadas tasas de maluso. Métodos: Estudio observacional transversal realizado en un servicio de urgencias de un hospital terciario. Pacientes adultos que acudían por distintas patologías fueron invitados a participar. Se evaluó la correcta indicación del IBP, además de su dosis, duración del tratamiento y facultativo prescriptor. Resultados: Se incluyeron 300 pacientes. La indicación se consideró correcta en 142 pacientes (47,3%), siendo la indicación más frecuente la profilaxis de enteropatía inducida por AINE/AAS (n=95; 31,7%). La «gastroprotección» en paciente polimedicados, sin fármacos gastroerosivos fue la principal indicación inadecuada (n=82; 27,3%) seguida de la profilaxis innecesaria en pacientes menores de 60 años tratados en monoterapia con un fármaco gastroerosivo. La mediana del tiempo de prescripción fue de 31 meses (RIC: 9-72) con un intervalo de 1-360 meses. El tiempo de prescripción era inferior en aquellos con indicación correcta (42,3 vs. 59,6 meses, p=0,02). El médico de atención primaria era el prescriptor más frecuente (n=165; 55%), seguido del gastroenterólogo (n=38; 12,7%), sin encontrar diferencias significativas en cuanto a la adecuación de la prescripción. Conclusiones: Estudios como el presente alertan de la persistencia de unas elevadas sobreutilización y maluso de los IBP. La desprescripción, cuando el IBP no está indicado, puede ayudar a controlar el gasto sanitario innecesario y a evitar iatrogenia (AU)

Introduction: Proton-pump inhibitors (PPI) are frequently prescribed for wide gastrointestinal disorders. The indications are well established, although a high rate of misuse has been reported. Methods: Observation cross-sectional study conducted a tertiary hospital. Adult patients who attended the emergency department were eligible. The appropriate indication was evaluated. Also, the prescription period, dosage and the prescribing clinician were reviewed. Results: 300 patients were included. The indication was adequate in 142 patients (47.3%). The main indication was the primary prophylaxis for NSAIDs/ASA-induced enteropathy (n=95 patients, 31.7%). Polypharmacy was the main misuse indication (n=82 patients, 27.3%). The median prescription duration was 31 months (IQR 9-72), ranging from one month to 360 months. The duration was lower in those with correct indication (42.3 vs 59.6 months, P=.02). The primary care physician was the main responsible for prescription (n=165 patients, 55%), followed by gastroenterologist (n=38 patients, 12.7%) without significant differences in appropriateness by speciality. Conclusions: Studies like this raise awareness about the PPI overuse and misuse. Deprescribing should be considered as essential to reduce iatrogenic risk and redundant health expenditure (AU)

The clinical impact of concomitant medication use on the outcome of postoperative recurrent non-small-cell lung cancer in patients receiving immune checkpoint inhibitors.

A recent study suggested that proton pump inhibitor (PPI) use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) was associated with poor clinical outcomes. However, the clinical impact of PPI use on the outcome of patients receiving ICIs for postoperative recurrent NSCLC is unknown. The outcomes of 95 patients with postoperative recurrence of NSCLC receiving ICIs at 3 medical centers in Japan were analyzed. We conducted adjusted Kaplan-Meier survival analyses with the log-rank test, a Cox proportional hazards regression analysis, and a logistic regression analysis using inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients' backgrounds. The IPTW-adjusted Kaplan-Meier curves revealed that the progression-free survival (PFS), but not the overall survival (OS), was significantly longer in patients who did not receive PPIs than in those who did receive them. The IPTW-adjusted Cox regression analysis revealed that PPI use was an independent poor prognostic factor for the PFS and OS. Furthermore, in the IPTW-adjusted logistic regression analysis, PPI non-use was an independent predictor of disease control. In this multicenter and retrospective study, PPI use was associated with poor clinical outcomes in patients with postoperative recurrence of NSCLC who were receiving ICIs. PPIs should not be prescribed indiscriminately to patients with postoperative recurrence of NSCLC who intend to receive ICIs. These findings should be validated in a future prospective study.

Use of acid-suppressive drugs and risk of fracture in children and young adults: a meta-analysis of observational studies.

BACKGROUND: Acid-suppressive drugs (ASDs) are being used by increasing number of children and young adults. However, evidence for a relationship between ASD use and the risk of fracture in these groups of patients is conflicting. We conducted a meta-analysis to evaluate the risk of fracture in children and young adults exposed to ASDs. METHODS: A literature search was performed using the PUBMED, EMBASE, and Cochrane Library databases from inception to November 2020. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated to determine the relationship of ASD use with fracture risk in children and young adults. RESULTS: Six studies reporting the outcomes of more than 900,000 children and young adults with ASD use were included in the meta-analysis. The pooled RR for fracture with the use of proton pump inhibitors (PPIs) versus non-use of these medications was 1.17 (95% CI = 1.1-1.25; P < 0.001) in children and 1.2 (95% CI = 0.87-1.65; P = 0.272) in young adults. By contrast, the use of histamine H2-receptor antagonists (H2RAs) was not significantly associated with fracture risk in children (RR, 1.08, 95% CI = 0.99-1.17; P = 0. 083) or young adults (RR, 1.08, 95% CI = 0.82-1.42; P = 0.589). Significant statistical and clinical heterogeneity among studies were determined for the main analysis and most of the subgroup analyses. CONCLUSIONS: Our study provides evidence linking PPI use to an increased risk of fracture in children. Thus, the use of PPIs in these patients should be carefully considered. However, randomized controlled studies are needed to determine causality and the role of unmeasured/residual confounding factors in this association.

Acid suppressant use in association with incidence and severe outcomes of COVID-19: a systematic review and meta-analysis.

PURPOSE: Several observational studies have presented conflicting results on the association between the use of proton pump inhibitors (PPIs) or histamine H2 receptor antagonist (H2RA) and the risk of coronavirus disease 2019 (COVID-19). This systematic review and meta-analysis aimed to examine this association. METHODS: In July 2021, PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for articles investigating the relationship between the two main acid suppressants and COVID-19. Studies showing the effect estimates as hazard ratio (HR) for severe outcomes or incidence of COVID-19 were evaluated using a random-effects model. RESULTS: A total of 15 retrospective cohort studies with 18,109 COVID-19 cases were included in the current meta-analysis. PPI use was significantly associated with severe outcomes of COVID-19 (hazard ratio [HR] = 1.53; 95% confidence interval [CI]: 1.20-1.95) but not with the incidence of COVID-19, whereas H2RA use was significantly associated with decreased incidence (HR = 0.86, 95% CI: 0.76-0.97). For subgroup analyses of PPIs, increased severe outcomes of COVID-19 were observed in < 60 years, active use, in-hospital use, and Asians. For subgroup analyses of H2RAs, decreased severe outcomes of COVID-19 were observed in > 60 years, while in-hospital use and use in Asia were associated with higher disease severity. CONCLUSIONS: Close observation can be considered for COVID-19 patients who use PPIs to prevent severe outcomes. However, caution should be taken because of substantial heterogeneity and plausible protopathic bias.

No association between acid suppressant use and risk of dementia: an updated meta-analysis.

PURPOSE: Findings from large observational studies on whether the use of acid suppressants increases the risk of dementia have been inconsistent. Since proton pump inhibitors (PPI) and histamine-2 receptor antagonists (H2RA) are the most commonly used acid suppressants in clinical practice, we performed a meta-analysis to examine the influence of PPI and H2RA on the risk of dementia. METHODS: A systematic search was performed on the PubMed, EMBASE, and Cochrane Library databases to identify studies published up to April, 2021. Studies that reported adjusted hazard ratio (HR) with 95% confidence intervals (CI) for the associations of interest were included. Data in the included studies were pooled using the random-effects model for meta-analysis. Statistical analysis was performed using Stata version 12.0 software. RESULTS: Seventeen studies involving 1,251,562 participants were included. It was found that PPI users were not likely to develop dementia compared with those not taking PPI (HR = 0.98, 95% CI: 0.85-1.13). Subgroup analysis based on publication year, location, mean age, duration of PPI use, and female proportion also revealed no association between PPI use and dementia risk. Similarly, H2RA use was not associated with the risk of dementia, as indicated by the pooled HR of 1.20 (95% CI: 0.98-1.47). CONCLUSION: Results of this meta-analysis suggest that PPI and H2RA do not increase the risk of dementia. These results may be used to inform the clinical application of acid suppressants. However, further randomized controlled trials are needed to confirm the present conclusions.

Proton pump inhibitors and osteoporosis risk: exploring the role of TRPM7 channel.

BACKGROUND: Long-term use of proton pump inhibitors (PPIs) has been linked to an increased risk of osteoporosis, with various indirect mechanisms so far identified. Although no direct underlying mechanism for effect on bone cells have been investigated with the use of PPIs. Melastatin-like transient receptor potential 7 (TRPM7)channel has been engaged in the proliferation of bone cells. TRPM7 channel is regulated by extracellular Mg2+ and Ca2+ level, that further encourages to analyse if any imbalance with pantoprazole usage could alter bone remodelling process mediated by TRPM7. OBJECTIVES: The present study was conducted to investigate the effect of pantoprazole on the calcium and magnesium level, the cations involved in the bone remodelling process, as well as role of the TRPM7 channel in the proliferation of bone cells. METHODS: A cytotoxicity study was carried out to study the effect of pantoprazole on the bone cell using MC3T3-E1 cell line, together with the expression of TRPM7 was determined post-pantoprazole treatment. An in vivo study in rats was carried out for estimation of Ca2+, Mg2+ and Ca2+/Mg2+ ratio as well as bone strength was measured over a duration of 4 weeks and 8 weeks with the treatment of pantoprazole. A pilot-scale clinical study was carried out in patients with a fracture to support the evidence of preliminary findings from in-vitro and in vivo studies. RESULTS: MC3T3-E1 cell line treated with pantoprazole showed decreased cell viability in a dose-dependent manner and reduced expression of TRPM7 channel, evidencing interaction of TRPM7 and pantoprazole in the bone remodelling process. A pilot study conducted on 12 patients having major fractures showed changes in serum Mg2+ and Ca2+ levels over a period of 1 month as well as the animal study also showed ionic imbalance over 8-week treatment with pantoprazole. Bone density measured for the patient at the end of the 1-month treatment was found to be in the osteopenic category, together with the animal study which showed a decrease in femur bone strength for the animal treated with pantoprazole over a period of 8 weeks. CONCLUSION: The study findings proved a negative impact of pantoprazole use on Ca2+ and Mg2+ levels, which can impact TRPM7-mediated bone remodelling which serves to be a possible mechanism for osteoporosis upon pantoprazole use.

Survival outcomes of patients with nonsmall cell lung cancer concomitantly receiving proton pump inhibitors and immune checkpoint inhibitors.

Recent evidence suggests that gut microbiota dysbiosis adversely affects the efficacy of immune checkpoint inhibitors (ICIs). Our objective was to investigate the association between concomitant use of proton pump inhibitors (PPIs) and ICIs, and poor prognosis in patients with nonsmall cell lung cancer (NSCLC). We conducted a cohort study using a completely enumerated lung cancer cohort from a nationwide healthcare database in South Korea. We identified 2963 patients treated with ICIs as second-line or later therapy for stage ≥IIIB NSCLC. PPI use was ascertained within 30-days before and on the date of ICI initiation, and nonuse was defined as no prescription of PPIs during this period. Using national vital statistics in South Korea, we assessed the risk of all-cause mortality associated with concomitant PPI use through a propensity score-matched Cox proportional hazard model. Among 1646 patients included after 1:1 propensity score-matching, concomitant PPI use was associated with a 28% increased risk of all-cause mortality, compared to nonuse (adjusted hazard ratio [HR] 1.28; 95% confidence intervals [CIs], 1.13-1.46). We observed an increased risk when we restricted the analysis to new users of PPI (adjusted HR = 1.64; 95% CI = 1.25-2.17). Subgroup analysis showed that PPI use was associated with high mortality risk among patients with viral hepatitis (adjusted HR = 2.72; 95% CI = 1.54-4.78; Pinteraction = .048). Our study indicates that PPI use is associated with poor prognosis in NSCLC patients treated with ICIs. Further prospective studies are required to determine the risk-benefit balance of concomitant use of PPIs and ICIs.

Effects of Proton Pump Inhibitors on the Small Bowel and Stool Microbiomes.

BACKGROUND: Proton pump inhibitor (PPI) use is extremely common. PPIs have been suggested to affect the gut microbiome, and increase risks of Clostridium difficile infection and small intestinal bacterial overgrowth (SIBO). However, existing data are based on stool analyses and PPIs act on the foregut. AIMS: To compare the duodenal and stool microbiomes in PPI and non-PPI users. METHODS: Consecutive subjects presenting for upper endoscopy without colonoscopy were recruited. Current antibiotic users were excluded. Subjects taking PPI were age- and gender-matched 1:2 to non-PPI controls. Subjects completed medical history questionnaires, and duodenal aspirates were collected using a validated protected catheter. A subset also provided stool samples. Duodenal and stool microbiomes were analyzed by 16S rRNA sequencing. RESULTS: The duodenal microbiome exhibited no phylum-level differences between PPI (N = 59) and non-PPI subjects (N = 118), but demonstrated significantly higher relative abundances of families Campylobacteraceae (3.13-fold, FDR P value < 0.01) and Bifidobacteriaceae (2.9-fold, FDR P value < 0.01), and lower relative abundance of Clostridiaceae (88.24-fold, FDR P value < 0.0001), in PPI subjects. SIBO rates were not significantly different between groups, whether defined by culture (> 103 CFU/ml) or 16S sequencing, nor between subjects taking different PPIs. The stool microbiome exhibited significantly higher abundance of family Streptococcaceae (2.14-fold, P = 0.003), and lower Clostridiaceae (2.60-fold, FDR P value = 8.61E-13), in PPI (N = 22) versus non-PPI (N = 47) subjects. CONCLUSIONS: These findings suggest that PPI use is not associated with higher rates of SIBO. Relative abundance of Clostridiaceae was reduced in both the duodenal and stool microbiomes, and Streptococcaceae was increased in stool. The clinical implications of these findings are unknown.

Efficacy and Safety of Antofloxacin-Based Triple Therapy for Helicobacter pylori Eradication Failure in China.

AIMS: Quinolone-containing triple therapy has been considered as the second-line therapy for eradication of Helicobacter pylori (H. pylori). At present, there are no data to show the efficacy and safety of antofloxacin-based rescue therapy for the eradication of H. pylori, and this pilot clinical trial was designed. METHODS: A total of 196 patients who failed H. pylori eradication using the clarithromycin-based or metronidazole-based triple or bismuth quadruple therapy were randomly allocated to one of the following rescue eradication therapy groups: AEA group (antofloxacin 200 mg once daily, esomeprazole 20 mg + amoxicillin 1000 mg twice daily) for 14 days, or LEA group (levofloxacin 500 mg once daily, esomeprazole 20 mg + amoxicillin 1000 mg twice daily) for 14 days. The minimal inhibitory concentrations were tested by the E-test method. The gyrA mutation was analyzed by sequencing. Follow-up 13/14C-urea breath test was examined at 1 month after discontinuation. RESULTS: A total of 178 eligible patients were included in this study. The eradication rate was significantly higher in AEA group than in LEA group according to both ITT (87.6% vs. 68.5%; P = 0.002) and PP analyses (90.7% vs. 70.1%; P = 0.001). ITT analyses indicated that the eradication rate was significantly higher in AEA group than in LEA group with Asn87 mutation (78.9% vs. 31.3%; P = 0.005) and levofloxacin-resistant strains (76.9% vs. 44.2%; P = 0.003). Two groups exhibited similar adverse event rates (AEA 14.6% vs. LEA 20.2%, P = 0.323). CONCLUSIONS: The findings showed that antofloxacin may be a promising candidate in rescue therapy for H. pylori eradication failure in China.

Adverse reactions related to proton pump inhibitors in pediatric population: an analysis of spontaneous reporting data.

BACKGROUND: The use of proton pump inhibitors (PPIs) has increased in the last 10 years in children. Data regarding their safety profile are limited. The aim of this study was to analyze data from the Italian spontaneous reporting system (SRS) database to evaluate the incidence and characteristics of PPI-related adverse drug reactions (ADRs) in children. RESEARCH DESIGN AND METHODS: This was an observational, retrospective study analyzing PPI-related ADR reports in children in the Italian SRS database between January 1st, 2001, and December 31st, 2020. ADRs were coded according to the system organ class term level. Factors associated with ADR seriousness were investigated. RESULTS: Seventy spontaneous reports of ADRs related to PPIs were analyzed. Esomeprazole and lansoprazole caused the highest number of ADRs equally (27% respectively), and the most frequently reported ADRs presented with gastrointestinal (24%) and/or skin manifestations (21.3%). More than a half of PPI prescriptions were off label for pediatric population. Serious ADRs were 19 (27.1%). Serious ADRs were more frequent in reports presenting PPIs combined with other drugs in comparison to reports with PPI single therapies (p = 0.03). CONCLUSIONS: PPI-related ADRs in children are mostly not serious, and combination therapy seems to be associated with ADR seriousness.

Effect of the Proton Pump Inhibitor Esomeprazole on the Systemic Exposure of Capecitabine: Results of A Randomized Crossover Trial.

Retrospective data suggest that gastric acid reduction by proton pump inhibitors (PPIs) impairs the dissolution and subsequent absorption of capecitabine, and thus potentially reduces the capecitabine exposure. Therefore, we examined prospectively the effect of esomeprazole on the pharmacokinetics of capecitabine. In this randomized crossover study, patients with cancer were assigned to 2 sequence groups, each consisting of 3 phases: capecitabine with esomeprazole administration 3 hours before (phase A), capecitabine alone (phase B), and capecitabine concomitant with cola and esomeprazole co-administration 3 hours before (phase C). The primary end point was the relative difference (RD) in exposure to capecitabine assessed by the area under the plasma concentration-time curve from zero to infinity (AUC0-inf ) and analyzed by a linear mixed effect model. Twenty-two evaluable patients were included in the analysis. After esomeprazole, there was a 18.9% increase in AUC0-inf of capecitabine (95% confidence interval (CI) -10.0% to 57.0%, P = 0.36). In addition, capecitabine half-life was significantly longer after esomeprazole (median 0.63 hours vs. 0.46 hours, P = 0.005). Concomitant cola did not completely reverse the effects observed after esomeprazole (RD 3.3% (95% CI -16.3 to 27.4%, P = 1.00). Capecitabine exposure is not negatively influenced by esomeprazole cotreatment. Therefore, altered capecitabine pharmacokinetics do not explain the assumed worse clinical outcome of PPI-cotreated patients with cancer.

The association between gut microbiome affecting concomitant medication and the effectiveness of immunotherapy in patients with stage IV NSCLC.

Several observational studies suggested that gut microbiome-affecting-medication impairs the effectiveness of immunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We postulated that if the effectiveness of immunotherapy is affected by drug-related changes of the microbiome, a stronger association between the use of co-medication and overall survival (OS) will be observed in patients treated with immunotherapy as compared to patients treated with chemotherapy. In a retrospective matched cohort study, immunotherapy patients were matched (1:1) to patients treated with chemotherapy in the pre immunotherapy era. The association between the use of antibiotics, opioids, proton pump inhibitors, metformin and other antidiabetics on OS was assessed with multivariable cox-regression analyses. Interaction tests were applied to investigate whether the association differs between patients treated with immuno- or chemotherapy. A total of 442 patients were studied. The use of antibiotics was associated with worse OS (adjusted Hazard Ratio (aHR) 1.39, p = 0.02) independent of the type of therapy (chemotherapy or immunotherapy). The use of opioids was also associated with worse OS (aHR 1.33, p = 0.01). The other drugs studied showed no association with OS. Interaction term testing showed no effect modification by immuno- or chemotherapy for the association of antibiotics and opioids with OS. The use of antibiotics and opioids is similarly associated with worse outcomes in both chemotherapy and immunotherapy treated NSCLC patients. This suggests that the association is likely to be a consequence of confounding rather than disturbing the composition of the microbiome.

Modifiable risk factors of ventilator-associated pneumonia in non-intensive care unit versus intensive care unit.

INTRODUCTION: Ventilator-associated pneumonia patients are treated in non-intensive care units because of a shortage of intensive care unit beds in Thailand. Our objective was to assess whether the type of unit and medications prescribed to the patient were associated with ventilator­associated pneumonia and multidrug resistant ventilator­associated pneumonia. METHODOLOGY: A matched case-control study nested in a prospective cohort of mechanical ventilation adult patients in a medical-surgical intensive care unit and five non-intensive care units from March 1 through October 31, 2013. The controls were randomly selected 1:1 with cases and matched based on duration and start date of mechanical ventilation. RESULTS: 248 ventilator-associated pneumonia and control patients were analyzed. The most common bacteria were multidrug resistant Acinetobacter baumannii (82.4%). Compared with patients in the intensive care unit, those in the neurosurgical/surgical non-intensive care units were at higher risk (p = 0.278). Proton pump inhibitor was a risk factor (p = 0.011), but antibiotic was a protective factor (p = 0.054). Broad spectrum antibiotic was a risk factor (p < 0.001) for multidrug resistant ventilator-associated pneumonia. CONCLUSIONS: Post-surgical and neurosurgical patients treated in non-intensive care unit settings were at the highest risk of ventilator-associated pneumonia. Our findings suggest that alternative using proton pump inhibitors should be considered based on the risk-benefit of using this medication. In addition, careful stewardship of antibiotic use should be warranted to prevent multidrug resistant ventilator-associated pneumonia.

Comparison of proton pump inhibitors and histamine 2 receptor antagonists for stress ulcer prophylaxis in the intensive care unit.

Proton pump inhibitors (PPIs), followed by histamine 2 receptor antagonists (H2RAs), are the most commonly used drugs to prevent gastrointestinal bleeding in critically ill patients through stress ulcer prophylaxis. The relative efficacy and drug-related adverse events of PPIs and H2RAs remain unclear. In this retrospective, observational, comparative cohort study, PPIs and H2RAs for stress ulcer prophylaxis in critically ill patients were compared using a common data model. After propensity matching, 935 patients from each treatment group (PPI or H2RA) were selected. The PPI group had a significantly higher 90-day mortality than the H2RA group (relative risk: 1.28; P = 0.01). However, no significant inter-group differences in the risk of clinically important gastrointestinal bleeding were observed. Moreover, there were no significant differences between the groups concerning the risk of pneumonia or Clostridioides difficile infection, which are known potential adverse events related to these drugs. Subgroup analysis of patients with high disease severity were consistent with those of the total propensity score-matched population. These findings do not support the current recommendations, which prefer PPIs for gastrointestinal bleeding prophylaxis in the intensive care unit.

Effectiveness of PPI treatment and guideline adherence in 236 patients with eosinophilic oesophagitis-Results from the population-based DanEoE cohort shows a low complication rate.

BACKGROUND: Proton pump inhibitors (PPIs) are often the first drug of choice in the treatment of eosinophilic oesophagitis (EoE), and in Denmark 8 weeks of high-dose PPI therapy is recommended as first-line treatment followed by rebiopsying, reflecting international recommendations. AIMS: To assess the population-based effectiveness of PPIs in the treatment of EoE and evaluate whether patients were treated and followed according to the regional guideline. METHODS: This is a retrospective, registry-based, DanEoE cohort study of 236 adult EoE patients diagnosed between 2007 and 2017 in the North Denmark Region. After patient file revision, the EoE diagnosis was defined according to the AGREE 2 consensus. Symptomatic PPI response was defined as complete symptom resolution and histological remission (<15 eosinophils per high-power field). RESULTS: PPI treatment was initiated in 92% of the EoE patients. High- and low-dose PPIs were prescribed in 55% and 45% of the cases, respectively. When treated with high-dose PPIs, 68% of the patients were completely symptom-free, and 49% were in histological remission. In 39% of high-dose PPI-treated patients, the symptomatic and histological responses were conflicting. While treated with PPIs, complications were rare, with <5% strictures in responders and <10% in non-responders. Rebiopsying was done in 67% of the EoE patients started on PPIs. CONCLUSIONS: High-dose PPI treatment was effective in half of the EoE patients started on PPIs, but conflicting symptomatic and histological PPI responses were common. Complications were rare when PPIs were started. One-third of the patients were not rebiopsied as recommended.

Proton pump inhibitors may contribute to progression or development of chronic obstructive pulmonary disease-A sequence symmetry analysis approach.

WHAT IS KNOWN AND OBJECTIVE: Proton pump inhibitors (PPIs), used to treat and prevent gastro-oesophageal conditions, are well-tolerated but have been associated with risk including pneumonia. The extent to which initiation of PPIs can contribute to other respiratory conditions such as chronic obstructive pulmonary disease (COPD) is largely unknown. METHODS: A sequence symmetry analysis (SSA) approach was applied to the Australian Department of Human Services, Pharmaceutical Benefits Scheme 10% extract. Participants were aged 45 years and older and were dispensed PPIs (ATC Codes A02BC01, A02BC02, A02BC03, A02BC04 and A02BC05) and long-acting bronchodilators (LABDs) for COPD (ATC Codes R03BB04 (PBS Item Code 10509D and 08626B), R03BB05, R03BB06, R03BB07 and R03AC18 (PBS Item Code 05137J and 05134F)) between 2013 and 2019. The analysis included patients initiated on an LABD within 12 months before or after their first prescription of a PPI. The crude sequence ratio (cSR) was calculated as the number of patients prescribed their first LABD after starting a PPI divided by the number of patients prescribed their first LABD before starting a PPI. Calculation of the adjusted sequence ratio (aSR) accounted for prescribing trends over time in initiation of each of the medicines. A signal was identified where the aSR lower 95% confidence interval (CI) was greater than one. RESULTS AND DISCUSSION: Initiation of omeprazole was associated with a 29% increased risk of initiating a LABD (ASR = 1.29 95% CI 1.22-1.36). Initiation of esomeprazole, rabeprazole, pantoprazole or lansoprazole was associated with 25%, 15%, 8% and 8% increased risk, respectively. WHAT IS NEW AND CONCLUSION: There is an established association between gastro-oesophageal reflux disease and COPD which has been confirmed by implementation of a sequence symmetry-based approach which demonstrated that PPI initiation is potentially associated with progression or exacerbation of COPD. The impact PPI use has directly on this association requires further investigation.

Two Different 1-Week Quadruple Therapies Given Back-to-Back Consecutive Therapy for Difficult-to-Treat Helicobacter pylori Infection: A Pilot Study.

INTRODUCTION: We aim to evaluate the efficacy of 2 different 1-week quadruple therapies given back-to-back consecutive therapy in patients with difficult-to-treat Helicobacter pylori infection. METHODS: Patients with proven H. pylori infection were recruited after >3 failed standard quadruple eradication. They received consecutive therapy consisting of esomeprazole 40 mg or rabeprazole 20 mg twice daily, amoxicillin 1,000 mg twice daily, tetracycline 500 mg 4 times daily, and furazolidone 100 mg 3 times daily for the first 7 days, followed by colloidal bismuth pectin 200 mg twice daily in place of furazolidone 100 mg for another 7 days. Eradication rates, treatment-emergent adverse events (TEAEs), and compliance were assessed. RESULTS: Sixty-five patients were enrolled. The mean number of previous eradications was 3.6 (range: 3-7). The intention-to-treat and per-protocol eradication rates were 90.8% (59/65) and 95.1% (58/61). In total, 23.4% (15/64) of patients experienced drug-related TEAEs. No serious adverse events were observed. None of the patients required treatment for TEAEs, and 95.3% (61/64) showed good compliance. Overall, 51 patients (78.5%) were with the available antimicrobial susceptibility testing results. The resistance rates to clarithromycin, metronidazole, levofloxacin, and amoxicillin were 60.8% (31/51), 100% (51/51), 70.6% (36/51), and 2.0% (1/51), respectively. No resistance was detected to either furazolidone or tetracycline. However, in 54.9% of patients (28/51), H. pylori was resistant to 3 antibiotics (metronidazole, levofloxacin, and clarithromycin). DISCUSSION: Consecutive therapy, including amoxicillin, tetracycline, and furazolidone, achieved a good eradication rate (>90%), with desirable compliance and tolerability in difficult-to-treat H. pylori infection.