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ABSTRACTBackgroundWe investigated if the addition of an inter-professional student-led medication review team (ISP-team) to standard care can increase the number of detected ADRs and reduce the number of ADRs 3 months after an outpatient visit.Research design and methodsIn this controlled clinical trial, patients were allocated to standard care (control group) or standard care plus the ISP team (intervention group). The ISP team consisted of medical and pharmacy students and student nurse practitioners. The team performed a structured medication review and adjusted medication to reduce the number of ADRs. Three months after the outpatient visit, a clinical pharmacologist who was blinded for allocation performed a follow-up telephone interview to determine whether patients experienced ADRs.ResultsDuring the outpatient clinic visit, significantly more (p < 0.001) ADRs were detected in the intervention group (n = 48) than in the control group (n = 10). In both groups, 60–63% of all detected ADRs were managed. Three months after the outpatient visit, significantly fewer (predominantly mild and moderately severe) ADRs related to benzodiazepine derivatives and antihypertensive causing dizziness were detected in the patients of the intervention group.ConclusionsAn ISP team in addition to standard care increases the detection and management of ADRs in elderly patients resulting in fewer mild and moderately severe ADRs.

Background: To evaluate the frequency, presentation, and course of the acute chest syndrome (ACS) in adult Afro-Caribbean patients with sickle cell disease (SCD). Patients and Methods: Retrospective cohort study during a 12-year period in patients with SCD at least 14 years of age, discharged with a diagnosis of ACS from the only hospital on the Caribbean island of Curacao, where 109 patients with SCD (62 HbSS, 47 HbSC) were observed. Results: Eighty-one episodes of ACS occurred (57 in 34 patients with HbSS and 24 in 19 patients with HbSC). The risk (odds ratio, 1.80; P=.13) and incidence (7.6 vs 4.2 per 100 patient-years; P>.2) of ACS did not differ between patients with HbSS and HbSC, but recurrent ACS affected patients with HbSS more (odds ratio, 2.96; P=.09). Abnormal chest sounds (mainly bilateral crepitations) were found in 91% of cases at diagnosis, but 48% had normal chest roentgenograms at that time and had delayed development (5.4 [+ or -] 3.4 days) of radiologic abnormalities. Patients with HbSS and HbSC had similar clinical presentations. Mortality (6%) and hospital stay (20 days) were not influenced by the use of transfusions or anticoagulation. All five nonsurviving female patients with HbSS had had more previous admissions for SCD and ACS. Conclusions: Acute chest syndrome occurs in 42% of adult Afro- Caribbean patients with SCD; patients with HbSS are more prone to recurrences. Delayed development of radiologic infiltrates is common. Interventions apart from supportive care do not influence the course of ACS. Fatal ACS occurs in patients with a more severe form of SCD. (Arch Intern Med. 1994; 154:557-561)

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OBJECTIVETo investigate whether the safety culture of a hospital unit is associated with the ability to improve.DESIGNQualitative investigation of safety culture on hospital units following a before-and-after trial on hand hygiene.SETTINGVU University Medical Center, a tertiary-care hospital in the Netherlands.METHODSWith support from hospital management, we implemented a hospital-wide program to improve compliance. Over 2 years, compliance was measured through direct observation, twice before, and 4 times after interventions. We analyzed changes in compliance from baseline, and selected units to evaluate safety culture using a positive deviance approach: the hospital unit with the highest hand hygiene compliance and 2 units that showed significant improvement (21% and 16%, respectively) were selected as high performing. Another 2 units showed no improvement and were selected as low performing. A blinded, independent observer conducted interviews with unit management, physicians, and nurses, based on the Hospital Survey on Patient Safety Culture. Safety culture was categorized as pathological (lowest level), reactive, bureaucratic, proactive, or generative (highest level).RESULTSOverall, 3 units showed a proactive or generative safety culture and 2 units had bureaucratic or pathological safety cultures. When comparing compliance and interview results, high-performing units showed high levels of safety culture, while low-performing units showed low levels of safety culture.CONCLUSIONSSafety culture is associated with the ability to improve hand hygiene. Interventions may not be effective when applied in units with low levels of safety culture. Although additional research is needed to corroborate our findings, the safety culture on a unit can benefit from enhancement strategies such as team-building exercises. Strengthening the safety culture before implementing interventions could aid improvement and prevent nonproductive interventions.Infect Control Hosp Epidemiol2017;38:1277–1283

IMPORTANCE: Inappropriate antimicrobial prescribing leads to antimicrobial resistance and suboptimal clinical outcomes. Changing antimicrobial prescribing is a complex behavioral process that is not often taken into account in antimicrobial stewardship programs. OBJECTIVE: To examine whether an antimicrobial stewardship approach grounded in behavioral theory and focusing on preserving prescriber autonomy and participation is effective in improving appropriateness of antimicrobial prescribing in hospitals. DESIGN, SETTING, AND PARTICIPANTS: The Dutch Unique Method for Antimicrobial Stewardship (DUMAS) study was a prospective, stepped-wedge, participatory intervention study performed from October 1, 2011, through December 31, 2015. Outcomes were measured during a baseline period of 16 months and an intervention period of 12 months. The study was performed at 7 clinical departments (2 medical, 3 surgical, and 2 pediatric) in a tertiary care medical center and a general teaching hospital in the Netherlands. Physicians prescribing systemic antimicrobial drugs for any indication for patients admitted to the participating departments during the study period were included in the study. INTERVENTIONS: We offered prescribers a free choice of how to improve their antimicrobial prescribing. Prescribers were stimulated to choose interventions with higher potential for success based on a root cause analysis of inappropriate prescribing. MAIN OUTCOMES AND MEASURES: Appropriateness of antimicrobial prescriptions was determined using a validated approach based on guideline adherence and motivated guideline deviation and measured with repeated point prevalence surveys (6 per year). Appropriateness judgment was masked for the study period. Antimicrobial consumption was extracted from pharmacy records and measured as days of therapy per admission. We used linear and logistic mixed-model regression analysis to model outcomes over time. RESULTS: A total of 1121 patient cases with 700 antimicrobial prescriptions were assessed during the baseline period and 882 patient cases with 531 antimicrobial prescriptions during the intervention period. The mean antimicrobial appropriateness increased from 64.1% at intervention start to 77.4% at 12-month follow-up (+13.3%; relative risk, 1.17; 95% CI, 1.04-1.27), without a change in slope. No decrease in antimicrobial consumption was found. CONCLUSIONS AND RELEVANCE: Use of a behavioral approach preserving prescriber autonomy resulted in an increase in antimicrobial appropriateness sustained for at least 12 months. The approach is inexpensive and could be easily transferable to various health care environments.

Background The relationship between lopinavir plasma concentration and the magnitude of lipid elevation after initiation of lopinavir/ritonavir-containing antiretroviral therapy is unclear. The aim of this study was to determine the relationship between drug concentration and lipid changes in two patient cohorts.Methods First, we analysed, in an outpatient cohort, the correlation between percentage lipid changes and lopinavir concentration, measured at least 2 weeks or more after initiation of lopinavir/ritonavir. Second, we analysed the correlation between lipid changes and lopinavir and ritonavir plasma concentrations in antiretroviral-naive patients enrolled in a trial comparing nevirapine plus lopinavir/ritonavir (533/133 mg twice daily) with zidovudine/lamivudine plus lopinavir/ ritonavir (400/100 mg twice daily).Results In 82 outpatients with 215 lopinavir plasma measurements, we found no significant correlations between lopinavir concentration and changes in lipids a median of 522 days after lopinavir/ritonavir initiation in univariable regression analyses, nor in multivariable analyses adjusting for potential confounders. In 40 trial samples collected 24 months after treatment initiation, the mean (95% CI) percentage increase in low-density lipoprotein cholesterol (LDLc) was significantly greater in the nevirapine/ lopinavir/ritonavir group (29.4% [16.8–43.3]) than in the zidovudine/lamivudine/lopinavir/ritonavir group (6.8% [-7.3–23.1]; P=0.03). However, the percentage LDLc change did not correlate with lopinavir or ritonavir concentration ratios (r=-0.25; P=0.17 and r=-0.06; P=0.75). Adding lopinavir or ritonavir concentrations into the multivariable regression analyses did not change the relation between LDLc change and randomized treatment.Conclusions Neither in an HIV outpatient clinic cohort nor in a trial comparing two lopinavir/ritonavir-containing therapies did we find any relation between changes in lipids, and lopinavir and ritonavir concentration, after initiating lopinavir/ritonavir-containing treatment.

ABSTRACTDirect detection of Streptococcus pneumoniaeDNA in blood adds to culture results in the etiological diagnosis of patients with community-acquired pneumonia (CAP). Quantification of the amount of DNA, the bacterial DNA load (BDL), provides a measurement of DNAemia that may increase the understanding of the clinical relevance of S. pneumoniaeDNA in blood. We evaluated the S. pneumoniaeBDL as a diagnostic tool in adult patients with CAP. The BDL was determined in whole-blood samples collected simultaneously with blood for culture from 45 adult patients with CAP. After DNA extraction, S. pneumoniaeDNA was detected with specific real-time PCR amplification, and the BDL was calculated with a standard curve. PCR and microbiological results were compared, and the BDL was related to clinical and laboratory parameters. S. pneumoniaeDNA was detected in 10/13 patients with positive blood cultures and in 67% of patients with microbiologically confirmed pneumococcal pneumonia. The positive predictive values of the receiver operating characteristic curves for the BDLs for pneumococcal infection (100%) and pneumococcal bacteremia (69%) were higher than those for the level of C-reactive protein (CRP; 43% and 23%, respectively) and the white blood cell count (WBC; 42% and 35%, respectively); the negative predictive values of these three parameters were in the same range (±90 and ±97%, respectively). The BDL was higher in patients presenting with systemic inflammatory response syndrome and in patients with bacteremia. Positive correlations were observed for the BDL with WBC, CRP level, and length of stay. We conclude that the BDL supports the diagnosis of S. pneumoniaeinfection in patients with CAP and provides a putative marker of the severity of disease.

Direct detection of Streptococcus pneumoniae DNA in blood adds to culture results in the etiological diagnosis of patients with community-acquired pneumonia (CAP). Quantification of the amount of DNA, the bacterial DNA load (BDL), provides a measurement of DNAemia that may increase the understanding of the clinical relevance of S. pneumoniae DNA in blood. We evaluated the S. pneumoniae BDL as a diagnostic tool in adult patients with CAP. The BDL was determined in whole-blood samples collected simultaneously with blood for culture from 45 adult patients with CAP. After DNA extraction, S. pneumoniae DNA was detected with specific real-time PCR amplification, and the BDL was calculated with a standard curve. PCR and microbiological results were compared, and the BDL was related to clinical and laboratory parameters. S. pneumoniae DNA was detected in 10/13 patients with positive blood cultures and in 67% of patients with microbiologically confirmed pneumococcal pneumonia. The positive predictive values of the receiver operating characteristic curves for the BDLs for pneumococcal infection (100%) and pneumococcal bacteremia (69%) were higher than those for the level of C-reactive protein (CRP; 43% and 23%, respectively) and the white blood cell count (WBC; 42% and 35%, respectively); the negative predictive values of these three parameters were in the same range (±90 and ±97%, respectively). The BDL was higher in patients presenting with systemic inflammatory response syndrome and in patients with bacteremia. Positive correlations were observed for the BDL with WBC, CRP level, and length of stay. We conclude that the BDL supports the diagnosis of S. pneumoniae infection in patients with CAP and provides a putative marker of the severity of disease.

ABSTRACTDirect detection of bacterial DNA in blood offers a fast alternative to blood culture and is presumably unaffected by the prior use of antibiotics. We evaluated the performance of two real-time PCR assays for the quantitative detection of Staphylococcus aureusbacteremia and for Enterococcus faecalisbacteremia directly in blood samples, without prior cultivation. Whole-blood samples for PCR were obtained simultaneously with blood cultures from patients admitted to the intensive care unit of our hospital. After the extraction of DNA from 200 µl of blood, real-time PCR was performed for the specific detection and quantification of S. aureusand E. faecalisDNA. The sensitivity for bacteremia of the S. aureusPCR was 75% and that of the E. faecalisPCR was 73%, and both tests had high specificity values (93 and 96%, respectively). PCR amplification reactions were positive for S. aureusfor 10 (7%) blood samples with negative blood cultures, and 7 (4%) PCR reactions were positive for E. faecalis. The majority of these PCR results were likely (50%) or possibly (42%) related to infection with the specific microorganism, based on clinical data and radiological and microbiological investigations. PCR results were concordant for 95% of paired whole-blood samples, and blood culture results were concordant for 97% of the paired samples. We conclude that the detection of S. aureusand E. faecalisDNA in blood by real-time PCR enables a rapid diagnosis of bacteremia and that a positive DNAemia is related to proven or possible infection with the specific microorganism in the majority of patients with negative blood cultures.

ABSTRACTRapid identification of microorganisms in blood cultures is required to optimize empirical treatment at an early stage. Fluorescence in situ hybridization (FISH) can reduce the time to identification of microorganisms in growth-positive blood cultures. In this study, we evaluated the performance, time to identification, and potential clinical benefits of FISH compared to those of conventional culture methods in routine practice. After Gram staining, blood culture fluids were simultaneously further identified with FISH and with conventional culture methods. Results and points in time of FISH and culture identification (provisional and final identifications) were collected and compared. For 91% of microorganisms, the genus or family name was identified, and for 79%, the species name could be attributed. The sensitivity and specificity of the individual probes exceeded 95%, except for the Enterobacteriaceaeprobe (sensitivity, 89%). Cross-hybridization was obtained with the Klebsiella pneumoniaeprobe for Klebsiella oxytoca. The time gains of FISH and final culture identification were more than 18 h for bacteria and 42 h for yeasts. With FISH, Staphylococcus aureuswas differentiated from coagulase-negative staphylococci 1.4 h faster than by provisional identification (P< 0.001). In conclusion, FISH allows rapid and reliable identification of the majority of microorganisms in growth-positive blood cultures. The substantial time gain of identification with FISH may allow same-day adjustment of antimicrobial therapy, and FISH is especially useful if no provisional identification is obtained. With further extension of the number of probes and a reduction in turnaround time, FISH will become a very useful diagnostic tool in the diagnosis of bloodstream infections.

ABSTRACTA number of antimycobacterial agents were evaluated with respect to their bacteriostatic activity (growth inhibition) versus the bactericidal activity against a clinical isolate of Mycobacterium avium(Mycobacterium aviumcomplex [MAC] strain 101) in relation to the time of exposure and the growth phase of the mycobacteria. In terms of growth inhibition the MAC in the active phase of growth was susceptible to clarithromycin, ethambutol, rifampin, amikacin, and the quinolones moxifloxacin, ciprofloxacin, and sparfloxacin. In terms of bactericidal activity in relation to the time of exposure these agents differed substantially with respect to the killing rate. An initial high killing capacity at low concentration was observed for amikacin, which in this respect was superior to the other agents. The bactericidal activity of clarithromycin and ethambutol was only seen at relatively high concentrations and increased with time. Killing by rifampin was concentration dependent as well as time dependent. The bactericidal activity of moxifloxacin was marginally dependent on the concentration or the time of exposure. The activity of clarithromycin in combination with ethambutol was not significantly enhanced compared to single-agent exposure. Only an additive effect was observed. The addition of rifampin or moxifloxacin as a third agent only marginally effected increased killing of MAC. However, by addition of amikacin the activity of the clarithromycin-ethambutol combination was significantly improved. The combination of amikacin and amoxicillin-clavulanic acid exhibited synergistic antimycobacterial activity. Towards MAC at low growth rates, only the quinolones exhibited a bactericidal effect.

Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment.

Background: Artemether is a new and effective treatment for malaria, although relapse is a problem in monotherapy. These relapses could be related to a time-dependent decline in artemether plasma levels described in multiple-dose studies and probably caused by autoinduction. The aim of this study was to evaluate the effect of grapefruit juice on the decreasing bioavailability over time of artemether.Methods: In a randomized, two-phase crossover study, eight healthy male subjects took 100 mg oral artemether with 350 mL water or with 350 mL double-strength fresh frozen grapefruit juice once daily for 5 days. On day 1 and day 5, 17 blood samples were collected over a period of 8 hours.Results: The mean peak artemether plasma concentration (Cmax) and the mean area under the concentration–time curve (AUC) after the last dose at day 5 were about one third compared with day 1, without a change in the elimination half-life after intake with water (P = .006 for Cmax; P = .005 for AUC) and with grapefruit juice (P < .001 for Cmaxand AUC). Grapefruit juice increased Cmax(P = .021) and AUC (P < .001) twofold on day 1 (P = .021) and day 5 (P = .05 for Cmax; P = .004 for AUC). Dihydroartemisinin, the active metabolite, showed a twofold increase in Cmax(P = .006) and AUC (P = .001) with grapefruit juice, without time-dependent changes of pharmacokinetic parameters.Conclusions: Grapefruit juice significantly increased the oral bioavailability of artemether but did not prevent the time-dependent reduction in bioavailability. It suggests that CYP3A4 in the gut wall is one of the metabolizing enzymes of artemether but seems to not be involved in the autoinduction process.

ABSTRACTWe evaluated a modified fluorescence in situ hybridization (FISH) assay for rapid (<1 h) identification of microorganisms in growth-positive blood cultures. The results were compared to those of the standard FISH technique and conventional culturing. The rapid identification of microorganisms with modified FISH can have important effects on clinical management of patients with bloodstream infections.

ObjectiveTo investigate whether a dog’s superior olfactory sensitivity can be used to detect Clostridium difficilein stool samples and hospital patients.DesignProof of principle study, using a case-control design. SettingTwo large Dutch teaching hospitals.ParticipantsA 2 year old beagle trained to identify the smell of C difficileand tested on 300 patients (30 with C difficileinfection and 270 controls).InterventionThe dog was guided along the wards by its trainer, who was blinded to the participants’ infection status. Each detection round concerned 10 patients (one case and nine controls). The dog was trained to sit or lie down when C difficilewas detected.Main outcome measuresSensitivity and specificity for detection of C difficilein stool samples and in patients.ResultsThe dog’s sensitivity and specificity for identifying C difficilein stool samples were both 100% (95% confidence interval 91% to 100%). During the detection rounds, the dog correctly identified 25 of the 30 cases (sensitivity 83%, 65% to 94%) and 265 of the 270 controls (specificity 98%, 95% to 99%).ConclusionA trained dog was able to detect C difficilewith high estimated sensitivity and specificity, both in stool samples and in hospital patients infected with C difficile.

The clinical significance of differences between antibiotics in endotoxin-liberating potential is unknown. Thirty patients with gram-negative urosepsis were randomized between imipenem and ceftazidime, which have, respectively, a low and a high endotoxin-liberating potential in vitro. In patients treated with ceftazidime, a slower defervescence was noticed. After 4 h of treatment, the blood endotoxin level decreased in all 3 endotoxemic patients receiving imipenem, whereas it increased in 2 of the 4 endotoxemic patients receiving ceftazidime, and in ceftazidime-treated patients, the endotoxin level in urine decreased less than in imipenem-treated subjects. Serum and urine cytokine levels increased 10%–40% after 4 h of ceftazidime treatment compared with no increase in the imipenem-treated patients (P > .05). Endotoxin release during antibiotic killing in vitro, assessed for all microorganisms, was to-fold higher with ceftazidime (P < .001). These results indicate that differences between antibiotics in endotoxin release may affect the inflammatory response during treatment.