Therapeutic Drug Monitoring Group Research Articles

Real-World Experience With Proactive Therapeutic Drug Monitoring During Infliximab Reintroduction.

Interruptions in infliximab therapy are associated with the development of antibodies to infliximab (ATI), infusion reactions (IRs), and loss of response. Despite these challenges, recent observational studies suggest that reinitiating infliximab after a drug holiday can be safe and effective. We assessed the utility of our protocol for restarting infliximab using early serum infliximab and ATI measurements. A retrospective cohort study of patients restarted on infliximab after at least a 6-month drug holiday. The cohort was divided into 2 groups: a "therapeutic drug monitoring (TDM) group," those who had serum infliximab and ATI measured 1-3 weeks after first reinduction dose, and a "non-TDM group." Outcomes included results of TDM, occurrence of immediate IR (IIR) and delayed hypersensitivity reactions, and medication persistence at 14 weeks and 1 year. About 76 patients were included: 49 in the TDM group and 27 in the non-TDM group. Of 76, 67 (88%) patients tolerated the first reinduction dose without IR. Formation of ATI was seen in 17 of 49 (35%) patients and was associated with longer drug holidays. Most did not experience IR during the entire therapy course-in 26 of 32 (81%) without ATI and 20 of 27 (74%) in the non-TDM group. Infliximab persistence at 14 weeks and 1 year was 76% and 57% for the cohort, respectively. Infliximab can be safely and effectively restarted after a drug holiday. We suggest performing TDM with a drug-tolerant assay 1-3 weeks after the first reinduction infusion as a means to identify patients at risk for severe IIR at the second dose.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases

Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). The primary end point was clinical remission at week 30. Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates. ClinicalTrials.gov Identifier: NCT03074656.

Proposal of initial and maintenance dosing regimens with linezolid for renal impairment patients

BackgroundLinezolid is administered as a fixed dose to all patients despite evidence of overexposure and thrombocytopenia in renal impairment. The aims of this study were to evaluate the risk of thrombocytopenia and the utility of therapeutic drug monitoring (TDM), and to propose alternate dosing regimens in patients with renal impairment.MethodsWe retrospectively reviewed patients ≥13 years old for whom serum linezolid trough concentration (Cmin) was measured during linezolid treatment. Patients with episodes of infection were divided into groups by presence of renal impairment (RI group) or absence of renal impairment (non-RI group), and by use of Cmin-based TDM (TDM group) or not (non-TDM group) during linezolid treatment.ResultsIn the 108 patients examined by multivariable analyses, renal impairment was independently associated with increased risk of thrombocytopenia (OR 3.17, 95%CI 1.10–9.12) and higher Cmin. Analysis of the utility of TDM in the RI group showed that clinical failure rate was significantly lower in the TDM subgroup than in the non-TDM subgroup. Furthermore, in the RI group, dosage adjustments were needed in 90.5% of the TDM subgroup. All episodes administered a reduced dose of 300 mg every 12 h in the RI group showed Cmin ≥ 2.0 mg/L. Additional analysis of 53 episodes in which Cmin was measured within 48 h after starting administration showed that the initial standard dose for 2 days was sufficient to rapidly reach an effective therapeutic concentration in the RI group.ConclusionsEmpirical dose reduction to 300 mg every 12 h after administration of the initial fixed dose for 2 days and Cmin-based TDM may improve safety outcomes while maintaining appropriate efficacy among patients with renal impairment.

Proactive therapeutic drug monitoring of adalimumab for pediatric Crohn's disease patients: A cost-effectiveness analysis.

Recent clinical findings showed proactive therapeutic drug monitoring (TDM) of adalimumab (ADL) to improve sustained remission rate in pediatric patients with Crohn's disease (CD). The present study aimed to evaluate the potential cost-effectiveness of proactive versus reactive TDM of ADL in pediatric patients with CD from the perspective of the US health-care provider. A Markov model was constructed to estimate outcomes of proactive versus reactive TDM of ADL in a hypothetical cohort of pediatric CD patients who were in remission on ADL maintenance treatment. Model inputs were derived from published literature and public data. Model outcomes included CD-related direct medical cost and quality-adjusted life-years (QALYs). Sensitivity analyses were performed to examine the robustness of base-case results. When compared with the reactive TDM group, the proactive TDM group saved 0.1960 QALYs at lower cost by USD2021 over a 3-year time frame in base-case analysis. One-way sensitivity analysis showed the ADL drug cost to be the most influential factor. Probabilistic sensitivity analysis of 10000 Monte-Carlo simulations found the proactive TDM group to gain 0.1958 QALYs (95% confidence interval [CI] 0.1950-0.1966; P<0.001) and save USD2037 (95%CI USD1943-2131; P<0.001). Proactive TDM for ADL seems to gain higher QALYs at lower cost in pediatric CD patients.

Evaluation of Therapeutic Drug Monitoring in the Clinical Management of Patients with Rheumatic Diseases: Data from a Retrospective Single-Center Cohort Study.

PurposeTreatment of rheumatic diseases with tumor necrosis factor inhibitors leads to improved clinical outcomes. Therapeutic drug monitoring (TDM) may assist in guiding clinical decisions. This study investigates the impact of TDM on clinical outcome, decision-making and biologics cost expenditure.Patients and MethodsIn a retrospective observational study of 306 patients with rheumatic diseases treated with four different tumor necrosis factor inhibitors, drug levels and antidrug antibodies were measured over a period of one year. Primary outcomes were the clinicians’ response to each TDM result and the clinical outcome two years after TDM initiation. Outcomes were compared between the 111 TDM-guided patients and the 195 empirically guided patients.ResultsTreatment change occurred in 55% of the patients in the TDM group, but in only 38% in the empirically guided group. In the TDM group, 89 (79.5%) patients were in remission or had low disease activity after two years follow-up compared to 128 (65.6%) patients in the empirical group. The average cost of biologics per patient per year was lower in the TDM group than in the empirical group for patients receiving infliximab, adalimumab or etanercept at baseline but not for golimumab.ConclusionTDM-guided decision-making is useful in rheumatic patients receiving TNFi and may optimize therapeutic decisions, leading to a better control of disease activity. Proactive TDM may support decisions on dose tapering, resulting in lower drug consumption and biologics cost expenditure.

Therapeutic Drug Monitoring Coupled With Bayesian Forecasting Could Prevent Vancomycin-Associated Nephrotoxicity in Renal Insufficiency Patients: A Prospective Study and Pharmacoeconomic Analysis.

Vancomycin is a critical antibiotic used in important infections, and therapeutic drug monitoring (TDM) is recommended. Bayesian forecasting is demonstrated to provide an approach that can improve trough concentration monitoring for dose adjustment. The objective of this study was to determine whether TDM coupled with a Bayesian approach could increase trough concentration target attainment and prevent vancomycin-associated nephrotoxicity in patients with renal insufficiency. A prospective study was performed using propensity score matching to provide covariate balance in renal insufficiency patients with gram-positive bacterial infections treated with vancomycin. Patients were divided into non-TDM (84 cases) and TDM (84 cases) groups, and their clinical outcomes were compared. The primary endpoints were probability of trough concentration target attainment and incidence of vancomycin-associated nephrotoxicity. A decision-tree model was developed to assess the cost effectiveness of TDM to prevent vancomycin-associated nephrotoxicity. Of the 168 eligible patients, 69 from each group (non-TDM and TDM) were matched based on propensity scores. In the matched cohort, trough concentration target attainment was higher with TDM (P = 0.003). Furthermore, reaching toxic trough concentrations was avoided (P = 0.027) in the TDM group. Multivariate logistic regression analysis confirmed that TDM practice independently reduced the incidence of vancomycin-associated nephrotoxicity in renal insufficiency patients (P = 0.021). According to this reduced nephrotoxicity, the incremental cost-effectiveness ratios of ¥22,638 per nephrotoxic episode prevented was found for vancomycin TDM. TDM coupled with Bayesian forecasting led to an increase in trough concentration target attainment and a decrease in the incidence of vancomycin-associated nephrotoxicity in renal insufficiency patients. In this high-risk population, TDM was demonstrated to be a cost-effective procedure.

Reduced nephrotoxicity with vancomycin therapeutic drug monitoring guided by area under the concentration–time curve against a trough 15–20 μg/mL concentration

Vancomycin is often employed as an antibacterial agent against Gram-positive bacteria, although dose-dependent nephrotoxicity is a concern. Although the risk may be reduced by therapeutic drug monitoring (TDM) guided by area under the concentration-time curve (an attempt to target an AUC > 400 μg•h/mL by Bayesian prediction: AUC400-guided TDM), the clinical efficacy of AUC400-guided TDM compared with trough concentration-guided TDM within 15-20 μg/mL (Trough15-20-guided TDM) has yet to be determined. We aimed to retrospectively evaluate the difference in the incidence rate of acute kidney injury (AKI), classified according to the Acute Kidney Injury Network, between these TDM groups. Individual AUC in the AUC400-guided TDM group was calculated by Bayesian prediction using trough and peak concentrations (within 3 h after the end of infusion). The AKI incidence in the Trough15-20-guided TDM group was 28.8% (15/52 patients) compared with an AKI incidence in the AUC400-guided TDM group of 9.1% (2/22 patients). Application of AUC400-guided TDM was identified as an independent factor for avoiding the incidence of AKI by Cox hazard regression analysis [hazard ratio=0.168, 95% confidence interval (CI) 0.034-0.839] and logistic regression analysis (odds ratio=0.037, 95% CI 0.003-0.285). As the estimated glomerular filtration rate (eGFR) improved, the surrogate target trough concentration for an AUC > 400 μg•h/mL was lowered (intercept 15.0074, slope -0.0598). In conclusion, AUC400-guided TDM may be superior to Trough15-20-guided TDM for the reduction of nephrotoxicity during vancomycin therapy.

Voriconazole therapeutic drug monitoring in critically ill patients improves efficacy and safety of antifungal therapy.

Since voriconazole plasma trough concentration (VPC) is related to its efficacy and adverse events, therapeutic drug monitoring (TDM) is recommended to perform. However, there is no report about the data of voriconazole TDM in critically ill patients in China. This retrospective study was performed to determine whether voriconazole TDM was associated with treatment response and/or voriconazole adverse events in critically ill patients, and to identify the potential risk factors associated with VPC. A total of 216 critically ill patients were included. Patients were divided into two groups: those underwent voriconazole TDM (TDM group, n=125) or did not undergo TDM (non-TDM group, n=91). The clinical response and adverse events were recorded and compared. Furthermore, in TDM group, multivariate logistic regression analysis was performed to identify the possible risk factors resulting in the variability in initial VPC. The complete response in the TDM group was significantly higher than that in the non-TDM group (P=.012). The incidence of adverse events strongly associated with voriconazole in the non-TDM group was significantly higher than that in the TDM group (19.8% vs 9.6%; P=.033). The factors, including age (OR 0.934, 95% CI: 0.906-0.964), male (OR 5.929, 95% CI: 1.524-23.062), serum albumin level (OR 1.122, 95% CI: 1.020-1.234), diarrhoea (OR 4.953, 95% CI: 1.495-16.411) and non-intravenous administration (OR 4.763, 95% CI: 1.576-14.39), exerted the greatest effects on subtherapeutic VPC (VPC<1.5mg/L) in multivariate analysis. Intravenous administration (OR 7.657, 95% CI: 1.957-29.968) was a significant predictor of supratherapeutic VPC (VPC>4.0mg/L). TDM can result in a favourable clinical efficacy and a lower incidence of adverse events strongly associated with voriconazole in critically ill patients. Subtherapeutic VPC was closely related to younger age, male, hyperalbuminaemia, diarrhoea and non-intravenous administration, and intravenous administration was a significant predictor of supratherapeutic VPC.

Prospective evaluation of improving fluoroquinolone exposure using centralised therapeutic drug monitoring (TDM) in patients with tuberculosis (PERFECT): a study protocol of a prospective multicentre cohort study

IntroductionGlobal multidrug-resistant tuberculosis (MDR-TB) treatment success rates remain suboptimal. Highly active WHO group A drugs moxifloxacin and levofloxacin show intraindividual and interindividual pharmacokinetic variability which can cause low drug exposure....

P645 Adalimumab drug monitoring is superior to empirical treatment adjustment in inflammatory bowel disease

Abstract Background Anti-TNF blockers are effective drugs in the treatment of inflammatory bowel disease (IBD). Therapeutic drug monitoring (TDM) of Adalimumab (ADA) may potentially improve clinical outcomes in this setting, but data are still scarce. Methods To compare ADA TDM and empirical treatment adjustment (ETA) in patients with IBD. Outcomes were evaluated at 2 years and included hospitalisation, surgery, treatment discontinuation, endoscopic remission and treatment failure (any unfavourable event). Single-centre retrospective study, including patients under ADA therapy. Results 103 patients were included, 86 with Crohn’s disease and 17 with ulcerative colitis. 52.4% male, mean age 28.5 (18–72). 56 patients received ADA TDM and 47 ETA. At 2-years, rates of treatment escalation (57.1% vs. 21.3%, p &amp;lt;0.001), mucosal healing (69.6% vs. 48.9%, p =0.032) and treatment discontinuation (17.9% vs. 4.3%, p =0.032) favored the TDM group. For TDM and ETA respectively, there was no statistically significant difference regarding need for hospitalisation (12.5% vs. 21.3%, p = 0.232), surgery (5.4% vs. 14.9%, p =0.103) and treatment failure (26.7% vs. 34.5%, p =0.395). Conclusion Our results suggest a benefit of TDM in achieving higher rates of mucosal healing The higher rates of treatment discontinuation suggest that TDM improves drug selection as patients switched unhelpful treatment earlier.

Early Therapeutic Drug Monitoring of Posaconazole Oral Suspension in Patients With Hematologic Malignancies.

Therapeutic drug monitoring (TDM) of posaconazole is usually performed 1 week after starting the drug because of its long half-life. However, previous studies showed that measuring the posaconazole plasma concentration (PPC) on day 3 is effective for predicting steady-state levels. The purpose of this study was to evaluate the relevance of early TDM (day 3) of posaconazole for achieving an optimal PPC. This prospective study was conducted from September 2014 to August 2016. A total of 148 patients with acute myeloid leukemia or myelodysplastic syndromes received a 200 mg posaconazole oral suspension 3 times daily for fungal prophylaxis. During the period from September 2014 to December 2015 (control group), no dose adjustment was performed on day 3. During the period from January 2016 to Aug 2016 (early TDM group), the frequency of posaconazole 200-mg administration was increased to 4 times daily in patients whose PPC on day 3 was <400 ng/mL. The cutoff value for optimal PPC on day 8 was defined as 500 ng/mL. In 21 of 107 patients (20%) in the control group, PPC was <400 ng/mL on day 3. In 15 (71%) of these 21 patients, the PPC was suboptimal on day 8. In the early TDM group, the PPC was <400 ng/mL on day 3 in 4 of 41 patients (10%). After increasing the posaconazole administration frequency in these 4 patients, PPC was suboptimal on day 8 in 1 patient (25%). In both groups, 104 patients had a PPC of ≥500 ng/mL on day 3, but 7% (7/104) of these had a suboptimal level on day 8. Early TDM on day 3 for posaconazole suspension may help more patients achieve optimal drug levels on day 8, although TDM on day 8 is needed even in patients with optimal levels on day 3.

The Effects of Fasting and Massive Diarrhea on Absorption of Enteral Vancomycin in Critically Ill Patients: A Retrospective Observational Study.

Although vancomycin (VCM) is not absorbed from healthy intestinal mucosa, elevations in the serum VCM concentrations have been reported in some cases. The aims of this study are to evaluate the necessity of therapeutic drug monitoring (TDM) during enteral VCM administration in critically ill patients. In this retrospective study, we enrolled 19 patients admitted to our intensive care unit who were treated with enteral VCM from December 2006 to January 2014. Clinical factors were compared between two groups: Group E whose serum concentrations were detectable, and Group N whose concentrations were below the detection limit of the VCM assay. Group E comprises 7 patients, and Group N comprises 12 patients. The fasting duration in Group E was significantly longer compared with that in Group N (17 vs. 8 days, p = 0.023). Furthermore, there was a significant correlation between the serum VCM concentrations and the fasting duration (r = 0.79, p < 0.0001), and the amount of diarrhea (r = 0.46, p = 0.046). No difference was observed in the amount of diarrhea at the time of TDM (Group E; 1,850 mL vs. Group N; 210 mL, p = 0.055) and in the Sequential Organ Failure Assessment subscore for the renal system at the time of TDM (Group E; 4.0 vs. Group N; 1.5, p = 0.068). Long durations of fasting and massive diarrhea were associated with elevations in the serum VCM concentrations, which suggested that TDM might be necessary during enteral VCM administration in critically ill patients. UMIN Clinical Trials Registry identifier UMIN000016955.

Evaluate Clinical Impact of Therapeutic Drug Monitoring of Phenytoin Monotherapy in Patient of Generalized Tonic Clonic Seizures

Background: Epilepsy is one of the most common serious disorders of the brain, affecting about 50 million people worldwide, 80% of the burden of epilepsy is in the developing world. Therapeutic drug monitoring (TDM) is one of the major arms to maximize efficacy and minimize risk of overdosing. AIM: To compare clinical outcome between monitored and unmonitored dose of Phenytoin in patient of generalized tonic clonic seizure. Methods: Comparative study of 40 patients on phenytoin with therapeutic drug monitoring verses 40 patients on phenytoin without therapeutic drug monitoring of Generalized tonic clonic seizure were undertaken. For therapeutic drug monitoring, early morning sample (before taking morning dose) was collected, centrifuged, plasma separated and after that therapeutic level are monitored using HPLC. Sampling was done twice a month for one month than once a month for third and sixth month; samples were also taken abruptly in case of poor or no response to therapy, any adverse effect if noted or if any patient taking other medication in between. Evaluation of Efficacy is done by mean Seizure frequency reduction and comparison of side effect profile of the two groups. Results: Statistically significant difference is seen in TDM and non-TDM Group at 3 and 6 months; with percent reduction of mean seizure frequency 85.44% in TDM group compared to 43.81% in non- TDM group. Conclusions: The results of this comparative evaluation after the collection of data and its analysis confirms clinical impact of therapeutic drug monitoring of phenytoin monotherapy in patients of generalized tonic clonic seizures.

P-012 YI Decisions to Dose Optimize Infliximab Using Pre-adjustment Therapeutic Drug Monitoring Result in Higher Trough Concentrations and Improved Endoscopic Outcomes

Increasingly, adequate infliximab (IFX) dosing is associated with improved outcomes in inflammatory bowel disease (IBD). Individualized therapeutic drug monitoring (TDM) to guide dose adjustment is cost-effective may offer clinical improvement. However, the effect of TDM-guided dose escalation on subsequent endoscopic outcomes remains unclear. We retrospectively evaluated the impact of TDM-driven dose adjustment on endoscopic remission. Data from primary responders to IFX who underwent dose escalation between 2008 and 2014 (interval reduction, dose increase or both) were reviewed. Patients with documented active endoscopic disease (ileal or colonic) <3 months prior to dose adjustment were included. 2 cohorts were examined: those with TDM-based decision to escalate and those with empiric decision. Outcomes recorded at median 6 months post- adjustment included endoscopic remission (Mayo <1, SES-CD <3), CRP, clinical remission and IBD-specific healthcare utilization (emergency visits, hospitalizations, steroid use, flares). TDM was performed using a homogenous mobility shift assay. Post-adjustment IFX and ATI concentration most discriminant for endoscopic remission were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission. Three hundred twelve dose optimization events were examined (149 TDM –based decision, 163 empiric). Patient demographics were not significantly different between groups apart from CRP ([mean ± SE] TDM: 23 ± 1.2; non-TDM: 11 ± 0.8 mg/L, P < 0.01). 63% of TDM group attained endoscopic remission compared to 48% non-TDM group (P < 0.05). 69% of the TDM group had significant clinical response compared to 57% non-TDM (P < 0.01) and also had fewer hospitalizations including ED visits (22% TDM versus 35% non-TDM group, P = 0.025). UC patients had a shorter time to optimization from first infusion (10 versus 20 months, P < 0.0001) and in the TDM group, had higher rates of endoscopic healing (64% compared to 46% CD) though this was not statistically significant. Median IFX trough levels increased significantly after TDM- based adjustment (from 1.5(pre) to 11 μg/mL (post); P < 0.0001) and were significantly higher than post-adjustment levels available in the empiric cohort (6.5 μg/mL, P = 0.015). Post-adjustment infliximab concentration of >4.5 μg/mL (area under the curve (AUC) = 0.8; 95% CI 0.71 to 0.88) and ATI concentration of <2.3 U/mL (AUC = 0.70; 95% CI 0.63 to 0.81) were associated with endoscopic remission. Multivariable analysis showed that IFX concentration (OR 1.2; [95% CI 1.1–1.3]; P < 0.0001) remained an independent predictor of endoscopic remission. TDM -guided dose adjustment is associated with higher post-adjustment trough levels, fewer ATI and in turn, higher endoscopic remission rates and fewer relapses.

The Clinical Significance of Voriconazole Therapeutic Drug Monitoring in Children With Invasive Fungal Infections

Voriconazole is an antifungal drug used to treat fungal infections. This was a retrospective study of 61 children with hemato-oncologic diseases or solid organ transplantation who were administered voriconazole for invasive fungal infections. Of the 61 patients, 31 (50.8%) were in the therapeutic drug monitoring (TDM) group, and 30 (49.2%) were in the non-TDM group. At 12 weeks, treatment failure rate in the non-TDM group was higher than the TDM group (78.6% versus 40.0%, p = 0.038). Drug discontinuation due to adverse events was less frequent in the TDM group than the non-TDM group (26.0% versus 92.3%, p = 0.001). Children required higher dosages to maintain drug levels within the targeted therapeutic range: an average of 8.3 mg/kg/dose in patients <12 years old and 6.9 mg/kg/dose for those ≥12 years old. Treatment failure rates were higher in patients whose voriconazole levels remained below 1.0 mg/L for more than 50% of their treatment duration than those above 1.0 mg/L (71.4% vs. 9.1% after 12 weeks, p = 0.013). Serial monitoring of voriconazole levels in children is important for improving treatment response and preventing unnecessary drug discontinuation. Higher dosages are needed in children to reach therapeutic range.

Optimization of time to initial vancomycin target trough improves clinical outcomes.

BackgroundOutcomes data for the efficacy of interventions designed to decrease the time to initial target vancomycin troughs are sparse.ObjectiveA vancomycin therapeutic drug monitoring (TDM) program was initiated to reduce the time to initial target troughs and to examine the impact on clinical outcomes.MethodsSingle-center, pre- and post-intervention observational study in a 250 bed teaching facility. Adult inpatients treated with physician-guided, vancomycin therapy (historical control, CTRL) were compared to high trough, pharmacist-guided vancomycin therapy (TDM). Nephrotoxicity analyses were conducted to the ensure safety of the TDM. Clinical outcome analysis was limited to patients with normal renal function and culture-confirmed gram positive infections and a pre-defined MRSA subset.Results340 patients met initial inclusion criteria for the nephrotoxicity analysis (TDM, n = 173; CTRL, n = 167). Acute kidney injury occurrence was similar between the CTRL (n = 20) and TDM (n = 23) groups (p = 0.7). Further exclusions yielded 145 patients with gram positive infections for clinical outcomes evaluation (TDM, n = 66; CTRL, n = 75). The time to initial target trough was shorter in the TDM group (3 vs. 5 days, p < 0.001). Patients in the TDM group discharged from the hospital more rapidly, 7 vs. 14 days (Hazards Ratio (HR), 1.41; 95% Confidence Interval [CI] 1.08–1.83; p = 0.01), reached clinical stability faster, 4 vs. 8 days (HR, 1.51; 95% CI 1.08–2.11; p = 0.02), and had shorter courses of vancomycin, 4 vs. 7 days (HR, 1.5; 95% CI 1.15–1.95; p = 0.003). In the MRSA infection subset (TDM, n = 36; CTRL, n = 35), patients in the TDM group discharged from the hospital more rapidly, 7 vs. 16 days (HR, 1.89; 95% CI 1.08–3.3; p = 0.03), reached clinical stability faster, 4 vs. 6 days (HR, 2.69; 95% CI 1.27–5.7; p = 0.01), and had shorter courses of vancomycin, 5 vs. 8 days (HR, 2.52; 95% CI 1.38–4.6; p = 0.003). Attaining initial target troughs in <5 days versus ≥5 days was associated with improved clinical outcomes. All cause in-hospital mortality, and vancomycin treatment failure occurred at comparable rates between groups.ConclusionsInterventions designed to decrease the time to reach initial target vancomycin troughs can improve clinical outcomes in gram positive infections, and in particular MRSA infections.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1146-9) contains supplementary material, which is available to authorized users.

The use of TDM in pregnant HIV-positive women: a retrospective cross-sectional review of five years practice in two large hospitals in Manchester.

IntroductionDespite plasma levels of certain HIV drugs decreasing in the third trimester of pregnancy there is no definitive evidence that therapeutic drug monitoring (TDM) improves HIV control and prevents mother-to-child transmission (MTCT). Indeed “one-off” TDM measurements are thought to poorly correlate with overall drug exposure [1]. We aim to describe baseline demographic and clinical characteristics of pregnant women with HIV, and to compare their HIV control, management during pregnancy and neonatal outcomes with respect to whether TDM was performed.Materials and MethodsRetrospective cross-sectional case note analysis was performed on pregnant women with HIV who attended North Manchester General Hospital and Manchester Royal Infirmary from 1st January 2008 to 28th May 2013.ResultsA total of 171 pregnancies were included; 39% (n=66) had TDM. The majority of patients were of African origin (85%) and age range was 16–42 years (median 32 years). TDM was found to be associated with a history of poor adherence to therapy (TDM 23%, vs no TDM 10%, p=0.017), although baseline viral load (VL) and CD4 counts were comparable between TDM and non-TDM groups (p=0.4756 and 0.9492, respectively). TDM was also associated with protease inhibitors (PI) (TDM 94% vs no TDM 77%, p= 0.004). Within the PI group, TDM was more strongly associated with atazanavir use than other PI's (55%, p=0.023). TDM was not associated with any other demographic variable or with either of the two hospital sites (p=0.427). TDM was associated with medication alterations during pregnancy (TDM 67% vs no TDM 13%, p=0.052), but was not associated with any difference in outcomes with similar proportions of newly detectable VL during pregnancy (TDM 12% vs no TDM 7%, p=0.220) and VL detectable at birth (TDM 14% vs no TDM 9%, p= 0.293). There were no instances of MTCT.ConclusionsTDM was associated with PI use and a history of poor adherence at baseline. TDM was not associated with improved HIV control during pregnancy and there was no MTCT. TDM was not shown to have any additional benefit in pregnancy and its routine use is not recommended to improve HIV control or reduce MTCT.

Benefits of therapeutic drug monitoring of vancomycin: a systematic review and meta-analysis.

Background and ObjectiveThe necessity of therapeutic drug monitoring (TDM) for vancomycin is controversial. The objective of the current review was to evaluate the available evidence for the necessity of TDM in patients given vancomycin to treat Gram-positive infections.MethodsMedline, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, CBM) were searched. Randomized controlled studies and observational studies that compared the clinical outcomes of TDM groups vs. non-TDM groups were included. Two reviewers independently extracted the data. The primary outcome was clinical efficacy of therapy. Secondary outcomes included vancomycin associated nephrotoxicity, duration of vancomycin therapy, length of hospital stay, and mortality. Meta-analysis was performed using the Mantel-Haenszel fixed effect method (FEM). Odds ratios (ORs) or weighted mean differences (WMD) with 95% confidence intervals (95%CIs) were calculated for categorical and continuous outcomes, respectively.ResultsOne randomized controlled trial (RCT) and five cohort studies were included in the meta-analysis. Compared with non-TDM groups, TDM groups had significantly higher rates of clinical efficacy (OR = 2.62, 95%CI 1.34–5.11 P = 0.005) and decreased rates of nephrotoxicity (OR = 0.25, 95%CI 0.13–0.48 P<0.0001). Subgroup analyses showed that TDM group had significantly higher rates of clinical efficacy in both cohort studies subgroup (OR = 3.04, 95%CI 1.34–6.90) and in Asian population subgroup (OR = 3.04, 95%CI 1.34–6.90). TDM group had significantly decreased rates of nephrotoxicity in all subgroup. There was no significant difference in duration of vancomycin therapy (WMD = −0.40, 95%CI −2.83–2.02 P = 0.74) or length of stay (WMD = −1.01, 95%CI −7.51-5.49 P = 0.76) between TDM and non-TDM groups. Subgroup analyses showed there were no differences in duration of vancomycin therapy. Only one study reported mortality rates.ConclusionsStudies to date show that TDM significantly increases the rate of clinical efficacy and decreases the rate of nephrotoxicity in patients treated with vancomycin.

The Effect of Therapeutic Drug Monitoring on Safety and Efficacy of Voriconazole in Invasive Fungal Infections: A Randomized Controlled Trial

Blood levels of voriconazole, a first line therapy for invasive aspergillosis, may correlate with adverse events and treatment response. However, no randomized controlled studies have been conducted to evaluate the clinical utility of routine therapeutic drug monitoring (TDM) of voriconazole. This study aimed to determine whether routine TDM of voriconazole reduces drug adverse events or improves treatment response in invasive fungal infections. This was a randomized, assessor-blinded, controlled, single center trial. One hundred ten adult patients were randomly assigned to TDM or non-TDM groups. In the TDM group, voriconazole dosage was adjusted (target range, 1.0-5.5 mg/L) according to the serum trough level measured on the fourth day after initiation of voriconazole. The non-TDM group received a fixed, standard dosage. Voriconazole-related adverse events were monitored, and treatment response was assessed three months after the initiation of therapy. Baseline characteristics including the CYP2C19 genotype were comparable between the two groups. While the incidence of adverse events was not different between the TDM group and the non-TDM group (both 42%; P = .97), the proportion of voriconazole discontinuation due to adverse events was significantly lower in the TDM group than in the non-TDM group (4% vs 17%; P = .02). A complete or partial response was observed in 81% (30 of 37) of patients in the TDM group compared to 57% (20 of 34) in the non-TDM group (P = .04). Routine TDM of voriconazole may reduce drug discontinuation due to adverse events and improve the treatment response in invasive fungal infections. NCT00890708.

Evidence-based TDM for antiretroviral drugs

Aim Evidence-based practice is essential to improving patient safety and the effectiveness of health care practices. The impact of therapeutic drug monitoring (TDM) on patients outcomes must be evaluated accordingly. Members of the ‘TDM group’ of the French Society of Pharmacology and Therapeutics worked together to address the role of TDM for various drugs. HIV protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) have been evaluated in this context.