Tachyphylaxis and reproducibility of desmopressin response in perioperative persons with nonsevere hemophilia A: implications for clinical practice.

Background: Desmopressin is frequently used perioperatively in persons with nonsevere hemophilia A. However, increase in factor (F)VIII:C after desmopressin use is interindividually highly variable. Tachyphylaxis has only been reported in test setting for persons with hemophilia A, with a remaining response of approximately 70% after a second dose compared with that after a first dose. Objectives: To study tachyphylaxis of FVIII:C response after multiple administration(s) of desmopressin in perioperative persons with nonsevere hemophilia A. Methods: We studied FVIII:C levels after desmopressin before (day 0 [D0]) and on days 1 (D1) and 2 (D2) after surgery in 26 patients of the DAVID and Little DAVID studies. We studied tachyphylaxis by comparing the responses at D1 and D2 with that at D0. We also assessed the reproducibility of the D0 response in comparison to an earlier performed desmopressin test. Results: The median absolute FVIII:C increase was 0.50 IU/mL (0.35-0.74; n = 23) at D0, 0.21 IU/mL (0.14-0.28; n = 17) at D1, and 0.23 IU/mL (0.16-0.30; n = 11) at D2. The median percentage of FVIII increase after the second administration (D1) compared with the first (D0) was 42.9% (29.2%-52.5%; n = 17) and that of the third (D2) compared with the first (D0) was 36.4% (23.7%-46.9%; n = 11). The FVIII:C desmopressin response at D0 was comparable with the desmopressin test response in 74% of the patients. Conclusion: Tachyphylaxis in the surgical setting was considerably more pronounced than previously reported, with FVIII:C at D1 and D2 of 36% to 43% of the initial response. Our results may have important implications for monitoring repeated desmopressin treatment when used perioperatively.

The effect of the acute phase of infection on absorption of and exposure to orally administered antibiotics in non-critically ill, hospitalized patients.

OBJECTIVES: During the acute phase of infection, IV antibiotics are preferred to ensure adequate systemic exposure. To assess whether adequate exposure may also be achieved with oral antibiotics, we investigated exposure to oral antibiotics and PTA during the acute phase of infection and after defervescence. METHODS: We enrolled hospitalized, non-critically ill febrile patients treated with IV antibiotics other than amoxicillin or ciprofloxacin. The study consisted of two visits: when patients had received <24 h IV treatment; and when patients had become afebrile. On both visits, patients received one additional dose of 750 mg amoxicillin, or 500 mg ciprofloxacin, depending on the presumed infection, after which serial blood samples were obtained. The primary endpoint was the ratio of the AUC during the febrile and the afebrile phase. The AUCs were considered to be equivalent when the ratio of the mean AUCs and its 90% CI was contained within the acceptance interval of 80%-125%. The secondary endpoint was PTA. RESULTS: Forty-four patients (15 amoxicillin, 29 ciprofloxacin) completed both study visits. The median time between the two study visits was 65.8 h (range 33.8-427.4). The ratio of the mean AUCs (study visit 1/study visit 2) was 97% (90% CI of 80%-117%) for amoxicillin and 112% (90% CI of 108%-116%) for ciprofloxacin. The PTA for amoxicillin and ciprofloxacin did not differ between the two phases and was adequate to treat common pathogens. CONCLUSIONS: The acute phase of infection in non-critically ill febrile patients does not influence the exposure to, or PTA of, orally administered amoxicillin and ciprofloxacin. This might justify earlier IV-to-oral switching.

Persistent Borrelia burgdorferi Sensu Lato Infection after Antibiotic Treatment: Systematic Overview and Appraisal of the Current Evidence from Experimental Animal Models.

Lyme borreliosis is caused by spirochetes belonging to the Borrelia burgdorferi sensu lato group, which are transmitted by Ixodes tick species living in the temperate climate zones of the Northern Hemisphere. The clinical manifestations of Lyme borreliosis are diverse and treated with oral or intravenous antibiotics. In some patients, long-lasting and debilitating symptoms can persist after the recommended antibiotic treatment. The etiology of such persisting symptoms is under debate, and one hypothesis entails persistent infection by a subset of spirochetes after antibiotic therapy. Here, we review and appraise the experimental evidence from in vivo animal studies on the persistence of B. burgdorferi sensu lato infection after antibiotic treatment, focusing on the antimicrobial agents doxycycline and ceftriaxone. Our review indicates that some in vivo animal studies found sporadic positive cultures after antibiotic treatment. However, this culture positivity often seemed to be related to inadequate antibiotic treatment, and the few positive cultures in some studies could not be reproduced in other studies. Overall, current results from animal studies provide insufficient evidence for the persistence of viable and infectious spirochetes after adequate antibiotic treatment. Borrelial nucleic acids, on the contrary, were frequently detected in these animal studies and may thus persist after antibiotic treatment. We put forward that research into the pathogenesis of persisting complaints after antibiotic treatment for Lyme borreliosis in humans should be a top priority, but future studies should most definitely also focus on explanations other than persistent B. burgdorferi sensu lato infection after antibiotic treatment.

Impact of mucositis on oral bioavailability and systemic exposure of ciprofloxacin Gram-negative infection prophylaxis in patients with haematological malignancies.

BACKGROUND: Patients with haematological malignancies frequently endure neutropenia and gastrointestinal (GI)-mucositis after high-dose chemotherapy. In these patients, ciprofloxacin is used for Gram-negative infection prophylaxis. OBJECTIVES: We investigate ciprofloxacin pharmacokinetics after oral administration in patients with haematological malignancies and explore the impact of GI-mucositis on oral bioavailability and clearance in order to assure adequate systemic exposure. METHODS: Adult haematological patients from two Dutch University Medical Centres received 500 mg twice daily oral ciprofloxacin for Gram-negative prophylaxis. The ciprofloxacin plasma concentrations were collected at various timepoints after oral ciprofloxacin administration and at various days after completion of chemotherapy. Data obtained after oral and intravenous ciprofloxacin administration in 28 healthy volunteers without mucositis served as a control group (391 samples). For haematological patients the degree of GI-mucositis was assessed using the Daily Gut Score (DGS), plasma citrulline and albumin. Data were analysed by non-linear mixed-effects modelling. RESULTS: In total, 250 blood samples were collected in 47 patients with a wide variety of haematological malignancies between 0-30 days after start of chemotherapy. Mucositis was generally mild [DGS median (IQR) 1 (1-1) and citrulline 16 µmol/L (12-23)]. The time to Cmax was slower in haematological patients compared with healthy volunteers although no association with the degree of mucositis (defined as DGS or citrulline) could be identified. Ciprofloxacin bioavailability and clearance were 60% and 33.2 L/h, respectively. CONCLUSIONS: This study supports oral dosing of ciprofloxacin as Gram-negative infection prophylaxis in haematological patients with mild-to-moderate mucositis capable of oral intake.

Impact of a vancomycin loading dose on the achievement of target vancomycin exposure in the first 24 h and on the accompanying risk of nephrotoxicity in critically ill patients.

BACKGROUND: The advocated pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin, AUC/MIC ≥ 400 mg·h/L, may not be reached with a conventional fixed starting dose of 1000 mg in critically ill patients, but increasing the dose may cause nephrotoxicity. OBJECTIVES: To evaluate the effect of a weight-based loading dose of 25 mg/kg vancomycin on PK/PD target attainment in the first 24 h (AUC0-24) in critically ill patients and to evaluate whether this increases the risk of acute kidney injury (AKI). PATIENTS AND METHODS: A prospective observational before/after study was performed in ICU patients, comparing the percentage of vancomycin courses with AUC0-24 ≥ 400 mg·h/L and the incidence of AKI, defined as worsening of the risk, injury, failure, loss of kidney function and end-stage kidney disease (RIFLE) score. The conventional dose group received 1000 mg of vancomycin as initial dose; the loading dose group received a weight-based loading dose of 25 mg/kg. A population PK model developed using non-linear mixed-effects modelling was used to estimate AUC0-24 in all patients. RESULTS: One hundred and four courses from 82 patients were included. With a loading dose, the percentage of courses achieving AUC0-24 ≥ 400 mg·h/L increased significantly from 53.8% to 88.0% (P = 0.0006). The percentage of patients with new-onset AKI was not significantly higher when receiving a 25 mg/kg loading dose (28.6% versus 37.8%; P = 0.48). However, the risk of AKI was significantly higher in patients achieving AUC0-24 > 400 mg·h/L compared with patients achieving AUC < 400 mg·h/L (39.0% versus 14.8%; P = 0.031). CONCLUSIONS: A weight-based loading dose of 25 mg/kg vancomycin led to significantly more patients achieving AUC0-24 ≥ 400 mg·h/L without increased risk of AKI. However, some harm cannot be ruled out since higher exposure was associated with increased risk of AKI.

Effect of an antibiotic checklist on length of hospital stay and appropriate antibiotic use in adult patients treated with intravenous antibiotics: a stepped wedge cluster randomized trial.

OBJECTIVES: Quality indicators (QIs) have been developed to define appropriate antibiotic use in hospitalized patients. We evaluated whether a checklist based on these QIs affects appropriate antibiotic use and length of hospital stay. METHODS: An antibiotic checklist for patients treated with intravenous antibiotics was introduced in nine Dutch hospitals in a stepped wedge cluster randomized trial. Prophylaxis was excluded. We included a random sample before (baseline), and all eligible patients after (intervention) checklist introduction. Baseline and intervention outcomes were compared. Primary endpoint was length of stay (LOS), analysed by intention to treat. Secondary endpoints, including QI performances, QI sum score (performance on all QIs per patient), and quality of checklist use, were analysed per protocol. RESULTS: Between 1 November 2014 and 1 October 2015 we included 853 baseline and 5354 intervention patients, of whom 993 (19%) had a completed checklist. The LOS did not change (baseline geometric mean 10.0 days (95% CI 8.6-11.5) versus intervention 10.1 days (95% CI 8.9-11.5), p 0.8). QI performances increased between +3.0% and +23.9% per QI, and the percentage of patients with a QI sum score above 50% increased significantly (OR 2.4 (95% CI 2.0-3.0), p<0.001). Higher QI sum scores were significantly associated with shorter LOS. Discordance existed between checklist-answers and actual performance. CONCLUSIONS: Use of an antibiotic checklist resulted in a significant increase in appropriateness of antibiotic use, but not in a reduction of LOS. Low overall checklist completion rates and discordance between checklist-answers and actual provided care might have attenuated the impact of the checklist.

Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy.

BACKGROUND: Although prothrombin complex concentrate (PCC) is often used to counteract vitamin K antagonist (VKA) therapy, evidence regarding the optimal dose for this indication is lacking. In Dutch hospitals, either a variable dose, based on body weight, target INR (international normalised ratio) and initial INR, or a fixed dose is used. AIM/OBJECTIVES: In this observational, pilot study, the efficacy and feasibility of the fixed dose strategy compared to the variable dosing regimen, is investigated. MATERIALS AND METHODS: Consecutive patients receiving PCC (Cofact®, Sanquin, Amsterdam) for VKA reversal because of a major non-cranial bleed or an invasive procedure were enrolled in two cohorts. Data were collected prospectively in the fixed dose group, cohort 1, and retrospectively in the variable dose regimen, cohort 2. Study endpoints were proportion of patients reaching target INR and successful clinical outcome. RESULTS: Cohort 1 consisted of 35 and cohort 2 of 32 patients. Target INR was reached in 70% of patients in cohort 1 versus 81% in cohort 2 (P = 0·37). Successful clinical outcome was seen in 91% of patients in cohort 1 versus 94% in cohort 2 (P = 1·00). Median INR decreased from 4·7 to 1·8 with a median dosage of 1040 IU factor IX (F IX) in cohort 1 and from 4·7 to 1·6 with a median dosage of 1580 IU F IX in cohort 2. CONCLUSION: This study suggests that a fixed dose of 1040 IU of F IX may be an effective way to rapidly counteract VKA therapy in our patient population and provides a basis for future research.