Serum vancomycin levels predict the short-term adverse outcomes of peritoneal dialysis–associated peritonitis

Background: The role of monitoring serum vancomycin levels during treatment of peritoneal dialysis (PD)–associated peritonitis is controversial. Substantial inter-individual variability may result in suboptimal serum levels despite similar dosing of vancomycin. The published predictors of suboptimal serum vancomycin levels remain limited. Methods: Data were retrospectively collected from 541 patients on continuous ambulatory peritoneal dialysis between 1 January 2018 and 31 December 312019. For gram-positive cocci and culture-negative peritonitis, we adopted a vancomycin administration and monitoring protocol. Short-term adverse outcomes of PD-associated peritonitis, including transfer to haemodialysis, death, persistent infection beyond planned therapy duration and relapse, were observed. The association between trough serum vancomycin levels and short-term adverse outcomes was evaluated. Results: Intraperitoneal vancomycin was used in 61 gram-positive cocci or culture-negative peritonitis episodes in 56 patients. Fourteen episodes of short-term adverse outcomes occurred in 12 patients, whose average trough serum vancomycin levels on day 5 of treatment were significantly lower than those who didn’t experience any adverse outcomes (8.4 ± 1.7 vs 12.5 ± 4.3 mg/L, p = 0.003). In gram-positive cocci or culture-negative peritonitis patients, those with higher day 5 trough serum vancomycin levels had a lower risk of short-term adverse outcomes (odds ratio: 0.6, 95% confidence interval: 0.4 to 0.9, p = 0.011). Receiver operating charecteristic curve (ROC) analyses showed that the day 5 trough serum vancomycin levels diagnostic threshold value for short-term adverse outcomes was 10.1 mg/L. After adjustments for gender, exchange volume and residual kidney function (RKF), baseline higher peritoneal transport was associated with a suboptimal (<10.1 mg/L) day 5 serum vancomycin level. Conclusions: Serum vancomycin levels are correlated with short-term adverse outcomes of PD-associated peritonitis, and higher peritoneal solute transport status is associated with suboptimal trough serum vancomycin levels on day 5.

Supratherapeutic Posaconazole Concentration in a Pediatric Transplant Patient With Confirmed Rhizopus Infection

There are a limited number of studies that guide dosing of posaconazole delayed-release (DR) tablets for the pediatric population. Current FDA-approved doses are only recommended for patients 13 years and older. For younger patients, providers are faced with the challenge of recommending posaconazole doses extrapolated from adult studies or choosing an alternative agent. We report on a case of a 10-year-old patient who experienced a supratherapeutic trough serum concentration and transaminitis after receiving the extrapolated adult dosage of posaconazole DR tablets (300 mg twice daily for the first day, followed by 300 mg daily) for 7 days. In the end, the patient required a smaller dose of 200 mg daily to achieve the desired trough target concentration for the treatment of a Rhizopus neck infection. Our findings highlight the need for additional studies to determine the optimal dosing of posaconazole DR tablets for children.

Optimal injection interval for testosterone undecanoate treatment of hypogonadal and transgender men

Objective: To define the optimized inter-injection interval of injectable testosterone undecanoate (TU) treatment for hypogonadal and transmen based on individual dose titration in routine clinical practice. Design and Methods: Prolective observational study of consecutive TU injections in men undergoing testosterone replacement therapy for pathological hypogonadism or masculinization of female-to-male transgender (transmen) subject to individual dosing titration to achieve a stable replacement regimen. Results: From 2006 to 2019, 6899 injections were given to 325 consecutive patients. After excluding the 6-week loading dose, 6300 injections were given to 297 patients who had at least three and a median of 14 injections. The optimal injection interval (mean of last three injection intervals), had a median of 12.0 weeks (interquartile range 10.4–12.7 weeks). The interval was significantly influenced by age and body size (body surface area, BSA) but not by diagnosis or trough serum LH, FSH and SHBG. Longer (≥14 weeks; 68/297, 23%), but not shorter (≤10 weeks; 22/297, 7.4%), intervals were weakly correlated with age but not diagnosis or other covariables. Low blood hemoglobin increased with trough serum testosterone to reach plateau once testosterone was about 10 nmol/L or higher. Conclusion: Optimal intervals between TU injection after individual titration resulted in the approved 12-week interval in 70% of patients with only minor influence for clinical application of age and body size (BSA) and not of trough serum LH, FSH and SHBG. Individually optimised inter-injection interval did not differ between men with primary or secondary hypogonadism or transmen.

P590 Which biomarkers have an effect on therapeutic vedolizumab drug levels? A retrospective analysis from a London Tertiary Centre

Background Vedolizumab is a humanised monoclonal antibody that binds to the α 4β 7 integrin and is an established treatment for both Crohn’s Disease (CD) and Ulcerative Colitis (UC). Drug levels for anti-tumour necrosis factor-α inhibitors such as infliximab and adalimumab have been used routinely for therapeutic drug monitoring (TDM). Target therapeutic levels for vedolizumab are yet to be established. Correlations with vedolizumab levels have been found in prospective and retrospective studies with a number of biomarkers such as C-Reactive Protein (CRP), albumin and Body Mass Index (BMI). However, these have failed to replicate consistently among studies of vedolizumab drug levels. Methods Trough serum vedolizumab drug levels were taken for 81 patients through a period of 3 months. These were analysed using a drug tolerant assay (IDKMonitor Drug level ELISA and IDKMonitor vedolizumab Free anti-drug antibody ELISA) run on a Dynex DS2 ELISA processor. These were collected from 33 CD patients, 46 UC patients and 2 patients with unclassified Inflammatory Bowel Disease (IBD-U). Faecal calprotectin (FCP) was collected in a subset of patients. Serum CRP, albumin, and haemoglobin (Hb) levels were also taken alongside levels. BMI was recorded at our infusion unit before receiving the infusion. Results 81 patients had drug levels taken: CD patients (mean drug level Q8w - 7.8 mcg/ml, Q4w - 18.6 mcg/ml, 9 patients with concomitant immunomodulators (CIM)), UC patients (mean drug level Q8w - 9.4 mcg/ml, Q4w – 22.0 mcg/ml, 5 patients with CIM), IBD-U (mean drug level Q8w - 15.2 mcg/ml, no patients with CIM). One patient developed anti-drug antibodies. Correlation was analysed using simple linear regression. A positive correlation was found with vedolizumab levels and albumin (correlation coefficient (r) = 0.11; p=0.03) but not with CRP (p=0.49), Hb (p=0.56), BMI (p=0.33) or FCP (p=0.08). Conclusion Our results indicate that albumin positively correlates with a higher vedolizumab drug level, which suggests that drug levels will be lower and perhaps less effective in patients with a low albumin level. Further studies should look at larger numbers of patients to identify whether the correlations identified with other biomarkers are significant and identify therapeutic target levels for vedolizumab. These will help guide TDM for patients and inform clinicians of when to switch as well as recognising likely non-responders and thus provide a personalised approach to biologic choice.

P442 Serum vedolizumab trough levels are associated with remission rate but not with extra-intestinal manifestations in IBD patients

Background The correlation between vedolizumab trough levels and inflammatory bowel diseases (IBD) remission rates has not yet been fully defined. We aimed to evaluate the association between vedolizumab serum trough levels and disease clinical and extra-intestinal manifestations (EIMs) and biomarker activity in IBD patients. Methods Forty-six patients (31 ulcerative colitis, 15 Crohn’s disease) who started vedolizumab therapy were retrospectively followed. Clinical and laboratory data were collected before treatment, during induction and maintenance until week 52 from initiation. Documentation of EIMs included peripheral and axial arthropathy, cutaneous and ocular manifestations and perianal disease. Clinical remission was defined as a Harvey-Bradshaw Index (HBI)&lt;5 or a Simple Clinical Colitis Activity Index (SCCAI)&lt;3. Biomarker normalization was defined as C-reactive protein level&lt;5 mg/L and fecal calprotectin level&lt;250 µg/g. Two-sample t-tests were used to find correlations between drug levels and disease activity. Results Higher week-2 trough serum vedolizumab levels were associated with week 14 clinical remission compared to patients with an active disease (30.55±2.22 µg/ml vs 22.28±3.57µg/ml, p=0.05) and with weeks-14 and -30 biomarker normalization (33.77±2.98 µg/ml vs 23.6±3.19 µg/ml, p=0.05 and 30.33±1.95 µg/ml vs 19.66±6.83 µg/ml, p=0.05, respectively). Week-6 vedolizumab levels were associated with week-30 clinical remission (30.52±3.48 µg/ml vs 15.35±4.94 µg/ml, p=0.03) and biomarker normalization (28.44±2.36 µg/ml vs 15.76±4.87µg/ml, p=0.02), and week 14 vedolizumab levels were associated week 30 biomarker normalization (14.81±1.64 µg/ml vs 6.23±2.25 µg/ml, p=0.03). Throughout the follow-up period, 24% of patients presented with EIMs (n=11). No association was found between vedolizumab levels and endoscopic outcomes or EIMs activity. Conclusion Trough serum vedolizumab levels at induction is associated with remission induction and maintenance but not with EIMs improvement. Assessment of early vedolizumab trough levels may be considered for prediction of response to therapy.

Target Attainment and Clinical Efficacy for Vancomycin in Neonates: Systematic Review

Vancomycin is commonly used as a treatment for neonatal infections. However, there is a lack of consensus establishing the optimal vancomycin therapeutic regimen and defining the most appropriate PK/PD parameter correlated with the efficacy. A recent guideline recommends AUC–guided therapeutic dosing in treating serious infections in neonates. However, in clinical practice, trough serum concentrations are commonly used as a surrogate PKPD index for AUC24. Despite this, target serum concentrations in a neonatal population remain poorly defined. The objective is to describe the relationship between therapeutic regimens and the achievement of clinical or pharmacokinetic outcomes in the neonatal population. The review was carried out following PRISMA guidelines. A bibliographic search was manually performed for studies published on PubMed and EMBASE. Clinical efficacy and/or target attainment and the safety of vancomycin treatment were evaluated through obtaining serum concentrations. A total of 476 articles were identified, of which 20 met the inclusion criteria. All of them evaluated the target attainment, but only two assessed the clinical efficacy. The enormous variability concerning target serum concentrations is noteworthy, which translates into a difficulty in determining which therapeutic regimen achieves the best results. Moreover, there are few studies that analyze clinical efficacy results obtained after reaching predefined trough serum concentrations, this information being essential for clinical practice.

Usefulness and Potential Pitfalls of Long-Acting Growth Hormone Analogs

Daily recombinant human GH (rhGH) is currently approved for use in children and adults with GH deficiency (GHD) in many countries with relatively few side-effects. Nevertheless, daily injections can be painful and distressing for some patients, often resulting in non-adherence and reduction of treatment outcomes. This has prompted the development of numerous long-acting GH (LAGH) analogs that allow for decreased injection frequency, ranging from weekly, bi-weekly to monthly. These LAGH analogs are attractive as they may theoretically offer increased patient acceptance, tolerability, and therapeutic flexibility. Conversely, there may also be pitfalls to these LAGH analogs, including an unphysiological GH profile and differing molecular structures that pose potential clinical issues in terms of dose initiation, therapeutic monitoring, incidence and duration of side-effects, and long-term safety. Furthermore, fluctuations of peak and trough serum GH and IGF-I levels and variations in therapeutic efficacy may depend on the technology used to prolong GH action. Previous studies of some LAGH analogs have demonstrated non-inferiority compared to daily rhGH in terms of increased growth velocity and improved body composition in children and adults with GHD, respectively, with no significant unanticipated adverse events. Currently, two LAGH analogs are marketed in Asia, one recently approved in the United States, another previously approved but not marketed in Europe, and several others proceeding through various stages of clinical development. Nevertheless, several practical questions still remain, including possible differences in dose initiation between naïve and switch-over patients, methodology of dose adjustment/s, timing of measuring serum IGF-I levels, safety, durability of efficacy and cost-effectiveness. Long-term surveillance of safety and efficacy of LAGH analogs are needed to answer these important questions.

Tacrolimus as a Possible Trigger of Tachycardias in a Heart-Transplanted Patient with Severe Diarrhea

Tacrolimus is a broadly used immunosuppressive agent in organ transplanted patients. It is known that it may induce arrhythmias. We here report on a heart transplanted patient with supraventricular and ventricular arrhythmias with an elevated tacrolimus trough serum level due to severe diarrhea.

Abstract 15682: A Novel Antibiotic Delivery Approach Enhances Salvage of Infected Cardiovascular-implantable Electronic Devices

Introduction: Infection of cardiovascular-implantable electronic devices (CIED) is a serious complication. Systemic antibiotic therapy is considered ineffective, justifying the current guidelines proposing total CEID and lead extraction. Objective: To evaluate the safety and efficacy of continuous in-situ-targeted, ultra-high concentration of antibiotics (CITA) in CIED infections limited to the subcutaneous pocket. Methods: Infected CIED were treated with CITA, delivered to the CIED pocket following minimally invasive surgery (MIS). The CIED were submerged in a 10 2 -10 3 minimal inhibition concentration (MIC) solution of vancomycin and/or gentamicin as per daily conventional dosing. Serum antibiotic levels were regulated by adjusting the concentration and flow of pocket irrigation. CIED salvage rate was assessed. Results: A total of 937 and 481serum assays of vancomycin and gentamicin, respectively, from 83 infected CIED was evaluated (Figure). Target antibiotic serum levels were obtained at 12-48 hours. Median treatment was 8 days (IQR 5,12). Parallel intravenous (IV) vancomycin treatment was applied in 6 (7%) infections. Vancomycin serum levels exceeded a trough limit of 20μg/ml in 20 (2.1%) assays, of which 19/20 received parallel IV treatment. No peak gentamicin levels were recorded. Gentamicin exceeded trough serum level reaching 2-3μg/ml in 80 (16.6%), reached potentially toxic levels of 3-5μg/ml in 33 (6.9%), and exceeded 5μg/ml in 10 (2.1%) assays. CITA resulted in a 1-year salvage of 71 (86%) CIED. Treatment failed in 12 infections, resulting in 8 uneventful total CIED extractions. The 30-day mortality rate was 2.4%. Conclusions: CITA provided ultra-high pocket antibiotic levels, with its safety confirmed by systemic level assays. CITA combined with MIS enabled salvage of 86% of infected CIED. The CITA-MIS approach may serve as an initial therapeutic option prior to the extraction of locally infected CIED, especially in high-risk patients.