Evaluation of Vancomycin Prediction Methods Based on Estimated Creatinine Clearance or Trough Levels.

BACKGROUND: The aim of this study was to investigate whether vancomycin clearance (CLva) can be adequately predicted with CLva prediction methods. Additionally, other covariates influencing the CLva were investigated and predictivity of monitoring of only trough levels to 24-hour area under the curve (AUC24) was evaluated. METHODS: Routine vancomycin plasma levels were measured with a fluorescence polarization immunoassay. Pharmacokinetic (PK) parameters of individual patients, that is, CLva and volume of distribution, were determined with maximum a posteriori Bayesian estimation. CLva was calculated with the 3 prediction methods, which are solely based on creatinine clearance (CLcr) estimated with Cockcroft and Gault formula and was compared with the calculated CLva with maximum a posteriori Bayesian estimation. Prediction errors were calculated. Correlations between CLva and CLcr, creatinine, age, weight, sex, and neutropenia were made. Furthermore, correlations between trough levels and AUC24 were evaluated. RESULTS: A total of 171 patients were included. Prediction errors and absolute prediction errors of the 3 methods ranged from 28% to 80% and 39% to 83%, respectively. In the multivariate analysis, CLva was significantly associated with CLcr, creatinine, age, weight, sex, and neutropenia. Linear correlation between AUC24 and trough levels was R(2) 0.38. CONCLUSIONS: Large prediction errors make the CLva algorithms based on estimated plasma CLcr unsuitable for use in patient care. Additionally, other factors, which are not accounted for in the current algorithms, influence the CLva individually. Owing to low association of AUC24 and trough levels, the AUC24 cannot be predicted with through levels. For a reliable AUC24 guided vancomycin dosing, therapeutic drug monitoring is necessary.

The ciprofloxacin target AUC : MIC ratio is not reached in hospitalized patients with the recommended dosing regimens.

AIM: The aim of this study was to determine the ciprofloxacin serum concentrations in hospitalized patients and to determine which percentage reached the efficacy target of AUC : MIC > 125. Additionally, the influence of demographic anthropomorphic and clinical parameters on the pharmacokinetics and pharmacodynamics of ciprofloxacin were investigated. METHODS: In serum of 80 hospitalized patients ciprofloxacin concentrations were measured with reverse phase high performance liquid chromatography with fluorescence detection. The ciprofloxacin dose was 400-1200 mg day(-1) i.v. in two or three doses depending on renal function and causative bacteria. Pharmacokinetic parameters were calculated with maximum a posteriori Bayesian estimation (MW\PHARM 3.60). A two compartment open model was used. RESULTS: Mean (± SD) age was 66 (± 17) years, the mean clearance corrected for bodyweight was 0.24 l h(-1) kg(-1) and the mean AUC was 49 mg l(-1) h. Ciprofloxacin clearance and thus AUC were associated with both age and serum creatinine. Of all patients, 21% and 75% of the patients, did not reach the proposed ciprofloxacin AUC : MIC > 125 target with MICs of 0.25 and 0.5 mg l(-1), respectively. A computer simulated increase in the daily dose from 800 mg to 1200 mg, decreased these percentages to 1% and 37%, respectively. CONCLUSION: A substantial proportion of the hospitalized patients did not reach the target ciprofloxacin AUC : MIC and are suboptimally dosed with recommended doses. Taking into account the increasing resistance to ciprofloxacin worldwide, a ciprofloxacin dose of 1200 mg i.v. daily in patients with normal renal function is necessary to reach the targeted AUC : MIC > 125.

Association of cytomegalovirus and other pathogens with frailty and diabetes mellitus, but not with cardiovascular disease and mortality in psycho-geriatric patients; a prospective cohort study.

BACKGROUND: Studies about associations of infections with herpes viruses and other pathogens, such as Chlamydia pneumoniae (CP) and Helicobacter pylori (HP) with cardiovascular disease (CVD), diabetes mellitus (DM), frailty and/or mortality are conflicting. Since high levels of antibodies against these pathogens occur in the elderly, the role of these pathogens in morbidity and mortality of vulnerable elderly was explored. RESULTS: Blood samples of 295 community dwelling psycho-geriatric patients were tested for IgG antibodies to herpes simplex virus type 1 and 2, varicella zoster virus, Epstein Barr virus (EBV), cytomegalovirus (CMV), human herpes virus type 6 (HHV6), CP and HP. Frailty was defined with an easy-to-use previously described frailty risk score. Relative risks (RR) with 95% confidence intervals were calculated to evaluate associations between CVD, DM, frailty and pathogens. Pathogens as a predictor for subsequent mortality were tested using Kaplan Meier analyses and Cox proportional hazard models. The mean age was 78 (SD: 6.7) years, 20% died, 44% were defined as frail, 20% had DM and 49% had CVD. Presence of CMV antibody titers was associated with frailty, as shown by using both qualitative and quantitative tests, RR ratio 1.4 (95% CI: 1.003-2.16) and RR ratio 1.5 (95% CI: 1.06-2.30), respectively. High IgG antibody titers of HHV6 and EBV were associated with DM, RR ratio 3.3 (95% CI: 1.57-6.49). None of the single or combined pathogens were significantly associated with mortality and/or CVD. CONCLUSIONS: Prior CMV infection is associated with frailty, which could be in line with the concept that CMV might have an important role in immunosenescence, while high IgG titers of HHV6 and EBV are associated with DM. No association between a high pathogen burden and morbidity and/or mortality could be demonstrated.

Narrow-spectrum antibiotics for community-acquired pneumonia in Dutch adults (CAP-PACT): a cross-sectional, stepped-wedge, cluster-randomised, non-inferiority, antimicrobial stewardship intervention trial.

BACKGROUND: Adults hospitalised to a non-intensive care unit (ICU) ward with moderately severe community-acquired pneumonia are frequently treated with broad-spectrum antibiotics, despite Dutch guidelines recommending narrow-spectrum antibiotics. Therefore, we investigated whether an antibiotic stewardship intervention would reduce the use of broad-spectrum antibiotics in patients with moderately severe community-acquired pneumonia without compromising their safety. METHODS: In this cross-sectional, stepped-wedge, cluster-randomised, non-inferiority trial (CAP-PACT) done in 12 hospitals in the Netherlands, we enrolled immunocompetent adults (≥18 years) who were admitted to a non-ICU ward and had a working diagnosis of moderately severe community-acquired pneumonia. All participating hospitals started in a control period and every 3 months a block of two hospitals transitioned from the control to the intervention period, with all hospitals eventually ending in the intervention period. The unit of randomisation was the hospital (cluster), and electronic randomisation (by an independent data manager) decided the sequence (the time of intervention) by which hospitals would cross over from the control period to the intervention period. Blinding was not possible. The antimicrobial stewardship intervention was a bundle targeting health-care providers and comprised education, engaging opinion leaders, and prospective audit and feedback of antibiotic use. The co-primary outcomes were broad-spectrum days of therapy per patient, tested by superiority, and 90-day all-cause mortality, tested by non-inferiority with a non-inferiority margin of 3%, and were analysed in the intention-to-treat population, comprising all patients who were enrolled in the control and intervention periods. This trial was prospectively registered at ClinicalTrials.gov, NCT02604628. FINDINGS: Between Nov 1, 2015, and Nov 1, 2017, 5683 patients were assessed for eligibility, of whom 4084 (2235 in the control period and 1849 in the intervention period) were included in the intention-to-treat analysis. The adjusted mean broad-spectrum days of therapy per patient were reduced from 6·5 days in the control period to 4·8 days in the intervention period, yielding an absolute reduction of -1·7 days (95% CI -2·4 to -1·1) and a relative reduction of 26·6% (95% CI 18·0-35·3). Crude 90-day mortality was 10·9% (242 of 2228 died) in the control period and 10·8% (199 of 1841) in the intervention period, yielding an adjusted absolute risk difference of 0·4% (90% CI -2·7 to 2·4), indicating non-inferiority. INTERPRETATION: In patients hospitalised with moderately severe community-acquired pneumonia, a multifaceted antibiotic stewardship intervention might safely reduce broad-spectrum antibiotic use. FUNDING: None.

Improving peak concentrations of a single dose regime of gentamicin in patients with sepsis in the emergency department.

OBJECTIVE: To achieve an optimal effect in patients with sepsis at the emergency department (ED), the gentamicin peak-concentration should be sufficiently high (i.e. peak-concentration/MIC ≥8-10). ICU patients with sepsis often need higher gentamicin doses to achieve sufficiently high peak-concentrations. The aim of this study is to investigate which dose is needed to reach adequate peak-concentrations in patients presenting with sepsis at the ED. METHODS: Patients with sepsis at the ED were included from August 2015 until February 2017. Peak-concentrations were measured in blood 30 minutes after the first gentamicin dose. The study consisted of three phases. In the first phase, peak-concentrations were measured after a standard dose of 5mg/kg. In the second phase, a simulation ((peak-concentration/actual dose) × simulated dose) was performed to determine which dose was needed to reach adequate gentamicin peak-concentrations of ≥16mg/L. In the third phase, peak-concentrations were measured for the best simulated dose. RESULTS: In phase one, of 86 patients who received a dose of 5mg/kg, 34 (39.5%) patients did not reach the target peak-concentration of ≥16mg/L, and 73 (84.9%) did not reach ≥20mg/L. In phase two, the simulation showed that with a dose of 7mg/kg 83 (96.5%) patients would reach peak-concentrations ≥16mg/L, and 67 (77.9%) of ≥20mg/L. In phase three, 53 patients received a dose of 7mg/kg, of whom 45 (84.9%) reached peak-concentrations of ≥16mg/L, and 31 (58.5%) of ≥20mg/L. CONCLUSION: Patients with sepsis at the ED need higher doses of gentamicin. A dose of 7mg/kg is needed to achieve adequate peak-concentrations in the majority of patients.

Vancomycin dosing in neutropenic patients.

BACKGROUND: To compare vancomycin pharmacokinetic parameters in patients with and without neutropenia. METHODS: Patients ≥18 years admitted on general wards were included. Routinely vancomycin trough and peak plasma concentrations were measured with a fluorescence polarization immunoassay. Pharmacokinetic parameters of individual patients were determined with maximum a posterior Bayesian estimation (MW Pharm 3.60). Neutropenia was defined as neutrophils <0.5×109 cells/L. PRINCIPAL FINDINGS: A total of 171 patients were included. Patients with neutropenia (n = 56) had higher clearance of vancomycin (CLva), 67 (±26) mL/min, compared to patients without neutropenia (n = 115), CLva 50 (±22) mL/min (p<0.001). No significant difference was found in serum creatinine and vancomycin volume of distribution. Neutropenia was positively associated with CLva, independently of relevant co-variables (B: 12.122, 95%CI: 1.095 to 23.149, p = 0.031). On average patients with neutropenia needed 33% higher doses of vancomycin to attain adequate exposure, i.e. AUC24≥400 mg×h/L. Furthermore, 15 initially neutropenic patients in our study group received vancomycin for a second administration period. Ten patients received the second administration period during another neutropenic period and 5 patients during a non-neutropenic phase. All 5 patients with vancomycin during both neutropenic and non-neutropenic phase had higher CLva (91 (±26) mL/min) during the neutropenic period and lower CLva (45 (±10) mL/min) during the non-neutropenic phase (p = 0.009). CONCLUSION: This study shows that most patients with neutropenia have augmented CLva. In a small group of patients that received vancomycin during two episodes, the augmented CLva seems to be reversible in the non-neutropenic period. Our data indicate that it is important to increase the daily dose with one third in patients with neutropenia (from 15 mg/kg twice daily to 13 mg/kg three times daily). Frequent performance of therapeutic drug monitoring in patients with neutropenia may prevent both therapy failure due to low AUCs and overcomes toxicity due to high vancomycin trough concentrations during recovery from neutropenia.

Is the standard dose of amoxicillin-clavulanic acid sufficient?

BACKGROUND: The pharmacodynamic (PD) efficacy target of amoxicillin is 40% time above the minimal inhibition concentration (40%T > MIC). Recent studies of other antibiotics have shown that PD-efficacy targets are not always reached. The aim of this study was to evaluate the percentage of hospitalised patients, using amoxicillin/clavulanic acid intravenously (iv), that reach the pharmacodynamic efficacy target 40%T > MIC. Additionally, the association of demographic anthropomorphic and clinical parameters with the pharmacokinetics and pharmacodynamics of amoxicillin were determined. METHODS: In serum of 57 hospitalised patients amoxicillin concentrations were measured using high performance liquid chromatography. Patients were older than 18 years and most patients had an abdominal infection. The standard amoxicillin/clavulanic acid dose was 4 times a day 1000/200 mg iv. Pharmacokinetic parameters were calculated with maximum a posteriori Bayesian estimation (MW\Pharm 3.60). A one-compartment open model was used. Individual dosing simulations were performed with MW\Pharm. RESULTS: In our study population, the mean (±SD) age was 67 (±16) years and the mean clearance corrected for bodyweight was 0.17 (±0.07) L/h/kg. Only, 65% of the patients reached the proposed amoxicillin 40%T > MIC with amoxicillin/clavulanic acid for bacterial MICs of 8 mg/L. A computer simulated increase of the standard dose to 6 times daily, increased this percentage to 95%. In this small study group 40%T > MIC was not associated with clinical or microbiological cure. CONCLUSION: A substantial proportion of the hospitalised patients did not reach the 40%T > MIC with the standard dose amoxicillin/clavulanic acid for a bacterial MIC of 8 mg/L. Therefore, we suggest increasing the standard dose of amoxicillin/clavulanic acid to 6 times a day in patients with severe Enterobacteriaceae infections. TRIAL REGISTRATION NUMBER: NTR1725 16th march 2009.

Trends in antibiotic prescribing in adults in Dutch general practice.

BACKGROUND: Antibiotic consumption is associated with adverse drug events (ADE) and increasing antibiotic resistance. Detailed information of antibiotic prescribing in different age categories is scarce, but necessary to develop strategies for prudent antibiotic use. The aim of this study was to determine the antibiotic prescriptions of different antibiotic classes in general practice in relation to age. METHODOLOGY: Retrospective study of 22 rural and urban general practices from the Dutch Registration Network Family Practices (RNH). Antibiotic prescribing data were extracted from the RNH database from 2000-2009. Trends over time in antibiotic prescriptions were assessed with multivariate logistic regression including interaction terms with age. Registered ADEs as a result of antibiotic prescriptions were also analyzed. PRINCIPAL FINDINGS: In total 658,940 patients years were analyzed. In 11.5% (n = 75,796) of the patient years at least one antibiotic was prescribed. Antibiotic prescriptions increased for all age categories during 2000-2009, but the increase in elderly patients (>80 years) was most prominent. In 2000 9% of the patients >80 years was prescribed at least one antibiotic to 22% in 2009 (P<0.001). Elderly patients had more ADEs with antibiotics and co-medication was identified as the only independent determinant for ADEs. CONCLUSION/DISCUSSION: The rate of antibiotic prescribing for patients who made a visit to the GP is increasing in the Netherlands with the most evident increase in the elderly patients. This may lead to more ADEs, which might lead to higher consumption of health care and more antibiotic resistance.