Association Between Use of Proton Pump Inhibitors and a Clostridium difficile-Associated Disease Outbreak: Case-Control Study

Background:

The use of proton pump inhibitors (PPIs) has been implicated as a potential contributor to the development of Clostridium difficile–associated disease (CDAD) because of the ability of these drugs to substantially reduce the bactericidal effect of gastric acid. This study focused on the impact of PPIs, among other known risk factors, during an outbreak of CDAD in a hospital setting.

Objectives:

The primary objective was to determine whether there was an association between current use of a PPI and the CDAD outbreak. Secondary objectives were to evaluate any correlations between the CDAD outbreak and past use of PPIs, use of antibiotics, diabetes mellitus, enteral feeding, cancer, gastrointestinal surgery, inflammatory bowel disease, and previous care or residence in an institutional setting.

Methods:

A retrospective case–control study was conducted. One hundred and fifty cases of hospital-acquired Clostridium difficile were identified. Patients were individually matched to controls for age, sex, date of admission to hospital, and hospital unit. The groups were compared with respect to each exposure.

Results:

Eight case patients could not be matched with suitable controls. Therefore, data from 142 cases and 142 controls were analyzed. There was no association between current use of a PPI and the CDAD outbreak (odds ratio [OR] 1.0, 95% confidence interval [CI] 0.99–1.01). Similarly, there was no correlation between the CDAD outbreak and diabetes, enteral feeding, cancer, gastrointestinal surgery, inflammatory bowel disease, or previous care or residence in an institution. However, the development of CDAD was positively associated with use of antibiotics within the 30 days preceding the infection (OR 12.0, 95% CI 4.0–35.7) and with past use of a PPI (OR 2.4, 95% CI 1.4–4.3).

Conclusions:

The development of CDAD during a hospital outbreak was associated with use of antibiotics and with past, not current, use of PPIs.     

Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes

AIMS

The efficacy of clopidogrel is influenced by CYP2C19 genotypes and substrates of CYP2C19, such as proton pump inhibitors (PPIs). We assessed the influence of three different PPIs on the anti-platelet function of clopidogrel in relation to CYP2C19 genotype status.

METHODS

Thirty-nine healthy volunteers with different CYP2C19 genotypes took clopidogrel 75 mg with or without omeprazole 20 mg, lansoprazole 30 mg or rabeprazole 20 mg in the morning for 7 days. The influence of the three PPIs on the anti-platelet function of clopidogrel was determined. A less than 30% inhibition of platelet aggregation (IPA) during clopidogrel dosing was defined as a ‘low responder’. We also examined whether evening dosing of omeprazole could prevent the interaction with clopidogrel dosed in the morning.

RESULTS

In rapid metabolizers (RMs, *1/*1, n = 15) of CYP2C19, omeprazole and rabeprazole significantly attenuated the anti-platelet function of clopidogrel. In decreased metabolizers (DMs, carriers of *2 and/or *3, n = 24), there was a large variation in IPA and there was a trend but no significant decrease in IPA when placed on a concomitant PPI. Some DMs became ‘low-responders’ when placed on a concomitant PPI. Evening omeprazole dose in RMs did not seem to cause a significant decrease in IPA in contrast to morning dosing, but did so in DMs.

CONCLUSIONS

The three PPIs affected the efficacy of clopidogrel to different degrees. Both omeprazole and rabeprazole significantly decreased IPA in RMs but not DMs, although there was a trend towards lower IPA in DMs. Morning and evening dosing of omeprazole were both associated with lower IPA in DMs.     

The influence of drug use in university hospitals on the pharmaceutical consumption in their surrounding communities

Aim

To investigate the influence of hospital drug choices on pharmaceutical consumption for nine competitive classes in the surrounding community.

Methods

Ecological study. Data from the national survey on drugs in hospitals were used to extract quantities purchased by 25 French university hospitals for three ‘hospital classes’ (EPOs, LMWHs and setrons) and six ‘ambulatory classes’ (PPIs, ACEIs and ARBs, statins, α-adrenoreceptor antagonists (AAAs) and selective serotonin re-uptake inhibitors SSRIs). Re-imbursed quantities for patients living in the hospital''s catchment area were extracted from the national health insurance database. The relationship between the use of a brand in hospitals and their catchment areas was assessed using multivariate linear regressions with instrumental variables.

Results

An increase of 1 day of treatment with one brand in the hospital was associated with a significant increase of 2.8 days of treatment with the same brand in the catchment area. However, results strongly varied according to classes. An increase of 1 day of treatment in the hospital was significantly associated with an increase of 0.21 day for ‘hospital classes’ and 21.8 days for ‘ambulatory classes’ in the catchment area. Strong variations were seen across ‘ambulatory classes’. The effect was maximal for cardiovascular classes and not significant for AAAs and SSRIs. The size of the effect also varied with hospital characteristics: small and proximity university hospitals exerted the greatest influence.

Conclusions

Hospital consumption influences the use of drugs in the community. A significant effect was found, especially for competitive classes used on a long-term basis. The economic consequences of these findings need to be addressed.     

Implementation of a Standardized Discharge Time-out Process to Reduce Prescribing Errors at Discharge

Background:

To reduce prescribing errors occurring on discharge from the hospital, a standardized discharge time-out process was implemented on a general medicine service at Wake Forest Baptist Medical Center. In the time-out process, the multidisciplinary care team reviewed the patient’s medical records together to determine the optimal discharge medication regimen. This regimen was recorded on a time-out form and then was used to develop the patient’s discharge documents.

Objective:

To evaluate the impact of a standardized discharge time-out process on prescribing errors that occur as patients are discharged from a general medicine service.

Methods:

The medical records of all patients discharged from a general medicine service during 60-day periods before (“pre-group”) and after (“post-group”) implementation of a standardized discharge time-out process were retrospectively reviewed by an internal medicine physician to determine the presence of discharge prescribing errors.

Results:

There were 142 and 124 evaluable patients in the pre- and post-groups, respectively. Compliance with the time-out process was 93% in the post-group. At least 1 prescribing error was detected in 49 (34.5%) of the discharges in the pre-group and 17 (13%) of the discharges in the post-group (P < .0001). All of the errors noted in the post-group occurred in discharges in which a clinical pharmacist was not involved.

Conclusions:

A multidisciplinary, standardized discharge time-out process was associated with a dramatic reduction in prescribing errors when patients were discharged from a general medicine service. The time-out process is one strategy to improve patient safety at hospital discharge.     

Proton pump inhibitor-induced acute interstitial nephritis

What is already known about this subject

• In several case reports the use of omeprazole has been associated with interstitial nephritis.
• Recently there have been reports linking other proton pump inhibitors (PPIs) with interstitial nephritis.

What this study adds

• We present supplementary cases received by the Netherlands Pharmacovigilance Centre Lareb, concerning interstitial nephritis in users of PPIs including omeprazole, pantoprazole and rabeprazole.
• In this case series seven patients are presented. In six cases they recovered spontaneously after cessation of the PPI, in one case the patient recovered after treatment with a corticosteroid.
• Further support for this association comes from the worldwide adverse drug reaction database of the World Health Organization.
• This report shows that interstitial nephritis can occur with all PPIs. Health professionals should be aware of this potential serious adverse drug reaction.

Aim

To investigate the association between the use of proton pump inhibitors (PPIs) and acute interstitial nephritis (AIN).

Methods

The Netherlands Pharmacovigilance Centre Lareb received seven case reports of AIN induced by various PPIs. In five of the reports it was mentioned that the diagnosis was confirmed by a renal biopsy.

Results

The time to onset varied between hours to 4 months. In all cases but one the patient spontaneously recovered after withdrawal of the offending agent. In one case the patient received treatment with prednisolone and recovered. In one patient a rechallenge was done 9 days after the initial event. Within 12 h of re-exposure the patient developed symptoms of AIN.

Conclusions

The mechanism of drug-induced AIN is unknown, but an immunological mechanism is suspected. Our reports show no relation between dosage, latency, time to recovery, age or gender, supporting the hypothesis that the aetiology of AIN is immunological. Lareb has received reports of AIN with the use of omeprazole, pantoprazole and rabeprazole. This shows that AIN is a complication associated with the whole group of PPIs and not only omeprazole. It is important for health professionals to be aware of this adverse drug reaction, because an accurate and timely diagnosis and withdrawal of the offending drug can prevent potentially life-threatening renal failure.     

Patients’ Recall of Interaction with a Pharmacist During Hospital Admission

Background

CSHP 2015 objective 1.5 proposes that at least 50% of recently hospitalized patients or their caregivers will recall speaking with a pharmacist while in the hospital.

Objective:

To determine the baseline prevalence of patients’ recall of interaction with a pharmacist during their hospital admission and their level of satisfaction with these encounters, following a major reorganization of health authorities in New Brunswick.

Methods:

Former inpatients from 27 units in 9 hospitals in the Horizon Health Network were randomly selected to complete a telephone survey within 5 to 7 months after discharge from hospital. Patients’ responses were validated against pharmacists’ documentation in the patients’ health records.

Results:

From June 2010 to July 2011, a total of 1028 former inpatients were screened, of whom 399 completed the telephone survey. More than half of the respondents were women (225 [56.4%]), and the mean age was 67 years. Overall, 184 patients (46.1%) recalled speaking with a pharmacist during their recent admission. Of these, 164 (89.1%) were “satisfied” or “very satisfied” with these interactions. In addition, 332 respondents (83.2%) indicated that if the hospital offered the opportunity to talk with a pharmacist who could help answer their questions about medications, they would take advantage of this service. The electronic hospital records of 181 patients (from 15 units at 3 sites) were analyzed to seek evidence of pharmacists’ interventions or encounters (e.g., medication history, consultation). Pharmacist documentation was found in the health records of 166 (91.7%) of all patients in this sample.

Conclusions:

Almost half of former inpatients recalled speaking with a pharmacist during a recent hospital admission. The majority of patients were satisfied with these interactions and would welcome future services from hospital pharmacists.     

Small-molecule modulators of the OX40–OX40 ligand co-stimulatory protein–protein interaction

Background and Purpose

The OX40–OX40L protein–protein interaction (PPI) is an important cell-surface signalling co-stimulatory regulator within the TNFR superfamily (TNFRSF) and a promising therapeutic target for immunomodulation. PPIs are difficult to modulate using small-molecules. Here, we describe the identification of a small-molecule OX40 modulator and confirm its partial agonist character.

Experimental Approach

Cell-free screening assays were developed and used to identify OX40–OX40L inhibitors. Modified versions of this assay were used to elucidate the binding partner and the binding nature of active compounds. OX40-transfected sensor cells with NF-κB reporters were constructed and used to confirm and characterize activity and specificity. Immunomodulatory activity and partial agonist nature were further confirmed by ex vivo T-cell polarization assays.

Key Results

Several compounds that concentration-dependently affected OX40-OX40L were identified. Cell assays indicated that they were partial agonists with low micromolar potency and adequate selectivity. Under polarizing conditions based on TGF-β, the most promising compound mimicked the effect of an agonistic anti-OX40 antibody in suppressing regulatory T-cell generation and diverting CD4⁺CD62L⁺Foxp3⁻ cells to T_H9 phenotype in vitro.

Conclusions and Implications

We identified, to our knowledge, the first small-molecule compounds able to interfere with OX40–OX40L binding and, more importantly, to act as partial agonists of OX40. This is particularly interesting, as small-molecule agonism or activation of PPIs is considered unusually challenging and there are only few known examples. These results provide proof-of-principle evidence for the feasibility of small-molecule modulation of the OX40–OX40L interaction and for the existence of partial agonists for TNFRSF-PPIs.     

Drug selection in French university hospitals: analysis of formularies for nine competitive pharmacological classes

AIM

To give a panorama of the selectivity and agreement of French university hospitals'' drug formularies (HDF) for nine competitive classes.

METHODS

All university hospitals were asked to send their HDF and selection criteria as of January 2009 for nine competitive pharmacological classes (proton pump inhibitors, serotonin antagonists, low molecular weight heparins, erythropoietins, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, statins, α-adrenoreceptor antagonists and selective serotonin re-uptake inhibitors). Selectivity of HDF was estimated by the percentage of drug entities selected by the hospital within the pharmacological class. Agreement between hospitals was assessed with modified kappa coefficients for multi-raters.

RESULTS

Twenty-one out of the 29 hospitals agreed to participate. These hospitals selected between 34% and 63% of the drug entities available for the nine classes, which represented 18 to 35 agents. Regarding the nature of chosen drug entities, the overall level of agreement was ‘fair’ and varied with pharmacological classes. Selection criteria were sent by only 12 hospitals. The technical component was the most important element in all hospitals. The weight of the economic component varied between 20% and 40% in the tender''s grade.

DISCUSSION

Large variations were seen in the number and nature of drugs selected by university hospitals which can be attributable to two successive decision-making processes (evaluation by the Drug and Therapeutics Committee followed by the purchasing process).     

Adherence to UK national guidance for discharge information: an audit in primary care

Aims

Poor communication of clinical information between healthcare settings is associated with patient harm. In 2008, the UK National Prescribing Centre (NPC) issued guidance regarding the minimum information to be communicated upon hospital discharge. This study evaluates the extent of adherence to this guidance and identifies predictors of adherence.

Methods

This was an audit of discharge summaries received by medical practices in one UK primary care trust of patients hospitalized for 24 h or longer. Each discharge summary was scored against the applicable NPC criteria which were organized into: ‘patient, admission and discharge’, ‘medicine’ and ‘therapy change’ information.

Results

Of 3444 discharge summaries audited, 2421 (70.3%) were from two teaching hospitals and 906 (26.3%) from three district hospitals. Unplanned admissions accounted for 2168 (63.0%) of the audit sample and 74.6% (2570) of discharge summaries were electronic. Mean (95% CI) adherence to the total NPC minimum dataset was 71.7% [70.2, 73.2]. Adherence to patient, admission and discharge information was 77.3% (95% CI 77.0, 77.7), 67.2% (95% CI 66.3, 68.2) for medicine information and 48.9% (95% CI 47.5, 50.3) for therapy change information. Allergy status, co-morbidities, medication history and rationale for therapy change were the most frequent omissions. Predictors of adherence included quality of the discharge template, electronic discharge summaries and smaller numbers of prescribed medicines.

Conclusions

Despite clear guidance regarding the content of discharge information, omissions are frequent. Adherence to the NPC minimum dataset might be improved by using comprehensive electronic discharge templates and implementation of effective medicines reconciliation at both sides of the health interface.     

Effectiveness of a medication reconciliation project conducted by PharmD students

Objectives

This study evaluated the effectiveness of a medication reconciliation program conducted by doctor of pharmacy (PharmD) students during an advanced pharmacy practice experience.

Methods

Patients admitted to medicine or surgery units at 3 hospitals were included. Students were instructed to interview each patient to obtain a medication history, reconcile this list with the medical chart, and identify and solve drug-related problems.

Results

Eleven students reconciled medications for 330 patients over 10 months and identified 922 discrepancies. The median number of discrepancies found per patient was 2, and no discrepancies were found in 25% of the cases. In cases in which discrepancies were identified, a greater number of medications had been prescribed for the patient (7.9 ± 4.0 medications compared to 5.4 ± 3.9 medications; p < 0.05). The students completed 59 interventions. Differences were found in the numbers of discrepancies and drug-related problems that different students at different sites identified (p < 0.05).

Conclusions

Pharmacy students provided a valuable service to 3 community hospitals. The students improved the quality of patient care by identifying and solving significant drug-related problems, identifying drug allergy information, and resolving home and admission medication discrepancies.     

Review of prescribing practices for intermittent bolus administration of morphine

Background:

Several changes to medication safety practices were proposed in a pediatric hospital, including changing the period of patient observation after administration of opioids and limiting the availability of various concentrations of morphine in the patient care unit.

Objective:

To document and review postoperative pain management for children on a surgical ward, specifically with regard to intermittent IV bolus administration of morphine, to help in assessing the impact of the proposed nursing practice changes.

Methods:

Data were collected from records for narcotics and controlled drugs for the surgical ward over a 3-month period (April to June 2006). For each patient, data had been recorded for up to 7 consecutive days after surgery. A patient’s data were included in the review if he or she had received at least 2 doses of morphine by IV bolus, except for the review of weight-based dosing pattern (mg/kg), for which all patients who had received at least one dose of IV morphine were included.

Results:

Charts for 193 patients were audited. Of these, 163 patients (84.5%) had recieved up to 0.1 mg/kg per dose, and 53 (27.5%) had received only one dose of morphine. Among patients who received more than one dose, the median dose was 0.080 mg/kg on day 1, with a decrease by day 5 to 0.065 mg/kg. Most patients received morphine over the first 2 days after surgery. The median time elapsed between doses was 4.3 h on day 1 and 6.2 h on day 2. Of the 1020 doses included in the analysis, most (801 [78.5%]) were 4 mg or less.

Conclusion:

The intermittent administration of IV bolus doses of morphine at the study hospital followed common standards for the treatment of postoperative pain. Most doses were no more than 4 mg. On the basis of this information, only 2-mg vials of morphine are now stocked on the ward. The hospital’s change in monitoring practices will increase the surveillance of patients receiving IV bolus doses of morphine.