Monitoring Of Serum Drug Levels Research Articles

AI Models to Assist Vancomycin Dosage Titration.

Background: Effective treatment using antibiotic vancomycin requires close monitoring of serum drug levels due to its narrow therapeutic index. In the current practice, physicians use various dosing algorithms for dosage titration, but these algorithms reported low success in achieving therapeutic targets. We explored using artificial intelligent to assist vancomycin dosage titration. Methods: We used a novel method to generate the label for each record and only included records with appropriate label data to generate a clean cohort with 2,282 patients and 7,912 injection records. Among them, 64% of patients were used to train two machine learning models, one for initial dose recommendation and another for subsequent dose recommendation. The model performance was evaluated using two metrics: PAR, a pharmacology meaningful metric defined by us, and Mean Absolute Error (MAE), a commonly used regression metric. Results: In our 3-year data, only a small portion (34.1%) of current injection doses could reach the desired vancomycin trough level (14–20 mcg/ml). Both PAR and MAE of our machine learning models were better than the classical pharmacokinetic models. Our model also showed better performance than the other previously developed machine learning models in our test data. Conclusion: We developed machine learning models to recommend vancomycin dosage. Our results show that the new AI-assisted dosage titration approach has the potential to improve the traditional approaches. This is especially useful to guide decision making for inexperienced doctors in making consistent and safe dosing recommendations for high-risk medications like vancomycin.

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

Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. ClinicalTrials.gov Identifier: NCT03074656.

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.

Diverse presentations of phenytoin toxicity-presenile cataract, encephalopathy and peripheral neuropathy: a case series

&lt;p class="abstract"&gt;One of the most commonly used antiepileptic drugs, phenytoin, has a narrow therapeutic index, high plasma protein binding, non-linear pharmacokinetics and inter-individual variability. It can also present with adverse drug reactions due to phenytoin toxicity with diverse presentations mimicking symptoms of other diseases thus causing diagnostic predicament. This case series reports three such cases of uncommon presentation of phenytoin toxicity like presenile cataract, fluctuating encephalopathy with diurnal variation and peripheral neuropathy. Monitoring of serum drug levels in such cases aids in confirming drug toxicity. Adverse drug reaction monitoring helps in early detection and appropriate management of drug related morbidity.&lt;/p&gt;

Interventions Targeting the Prescribing and Monitoring of Vancomycin for Hospitalized Patients: A Systematic Review Protocol.

IntroductionVancomycin remains one of our essential antibiotics after fifty years of treating serious infections such as methicillin-resistant Staphylococcus aureus. Vancomycin, unlike many other antibiotic agents, requires individualized dosing and monitoring of serum drug levels to ensure it is efficacious, to minimize toxicity, and to limit the development of antibiotic resistance. These issues have led to numerous vancomycin clinical practice guidelines being published in recent years including several key national guidelines. Significant resources are invested during the development of such guidelines; however, there is often little or no information about how such guidelines or other vancomycin practice improvement initiatives should be implemented. The aim of this systematic review is to identify and evaluate the effect of interventions using education, guideline implementation, and dissemination of educational resources that have sought to improve therapeutic drug monitoring and dosing of vancomycin.MethodsA systematic review of the literature will be conducted for RCTs and observational studies where a vancomycin guideline or practice improvement initiative has been implemented. Electronic databases to be searched are PubMed, Medline, CINAHL, EMBASE and the Cochrane Library of Systematic Reviews. The population will be patients who have had intravenous vancomycin prescribed and monitored in hospital. The interventions will be education, implementation of guidelines or protocols, dissemination of educational materials (printed or electronic) or multifaceted interventions of the above. The comparator will be patients who have had standard-care prescribing and monitoring of vancomycin. Outcomes will be changes in prescribing and ordering of vancomycin serum tests, and serum levels attained in patients as well as reported nephrotoxicity. Two reviewers will be involved in the quality assessment and extraction of data. The Scottish Intercollegiate Guidelines Network checklist for RCTs will be used. Studies that are not randomized will be assessed for quality using the validated ROBINS-I (risk of bias in non-randomized studies of interventions) tool.DiscussionThis systematic review will identify interventions that have been used to implement guidelines and clinical practice initiatives for vancomycin. The findings of this review may be informative to those involved with the implementation of vancomycin clinical practice guidelines. Systematic review registration: PROSPERO: CRD42016049147.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-017-0177-7) contains supplementary material, which is available to authorized users.

Probable Nonconvulsive Status Epilepticus With the Use of High-Dose Continuous Infusion Ceftazidime

Multidrug resistant (MDR) bacterial infections are a major concern of health care providers due to their increasing incidence and associated mortality. In some cases, few or no antibiotics have preserved activity. Beta-lactam administration via continuous infusion can optimize time over minimum inhibitory concentration (MIC). In some cases, use of high-dose continuous infusion (HDCI) may be necessary to achieve serum levels in excess of nonsusceptible MIC values. The use of HDCI beta-lactams is not without risk, specifically neurotoxic adverse effects, which appear dose related. We describe a 64-year-old male who experienced myoclonus and nonconvulsive status epilepticus while receiving HDCI ceftazidime for treatment of multidrug resistant Pseudomonas aeruginosa bacteremia. This report serves as a cautionary example of the potential toxicities associated with HDCI beta-lactams and supports the importance of risk–benefit analysis prior to and during treatment. Additionally, the use of serum drug level monitoring may be necessary to better prevent or predict toxicity.

Metabolic manipulation in chronic heart failure: study protocol for a randomised controlled trial

BackgroundHeart failure is a major cause of morbidity and mortality in society. Current medical therapy centres on neurohormonal modulation with angiotensin converting enzyme inhibitors and β-blockers. There is growing evidence for the use of metabolic manipulating agents as adjunctive therapy in patients with heart failure. We aim to determine the effect of perhexiline on cardiac energetics and alterations in substrate utilisation in patients with non-ischaemic dilated cardiomyopathy.MethodsA multi-centre, prospective, randomised double-blind, placebo-controlled trial of 50 subjects with non-ischaemic dilated cardiomyopathy recruited from University Hospital Birmingham NHS Foundation Trust and Cardiff and Vale NHS Trust. Baseline investigations include magnetic resonance spectroscopy to assess cardiac energetic status, echocardiography to assess left ventricular function and assessment of symptomatic status. Subjects are then randomised to receive 200 mg perhexiline maleate or placebo daily for 4 weeks with serum drug level monitoring. All baseline investigations will be repeated at the end of the treatment period. A subgroup of patients will undergo invasive investigations with right and left heart catheterisation to calculate respiratory quotient, and mechanical efficiency. The primary endpoint is an improvement in the phosphocreatine to adenosine triphosphate ratio at 4 weeks. Secondary end points are: i) respiratory quotient; ii) mechanical efficiency; iii) change in left ventricular (LV) function.Trial RegistrationClinicalTrials.gov: NCT00841139ISRCTN: ISRCTN2887836

Endemic Fungal Infections in Solid Organ Transplant Recipients

Endemic Fungal Infections in Solid Organ Transplant Recipients

Generic substitution of antiepileptic medications in patients with epilepsy: Is this a potential problem?

The question “Is there a difference between brand and generic formulations?” is often proposed to health care professionals, particularly pharmacists. This topic is controversial among pharmacists, physicians, legislative groups, and third-party payers. More than 7000 generic products have been approved for marketing thus far, and approvals are now occurring at a rate exceeding 500 per year,1 increasing the possibility for drug switchability (defined as the process of switching from an innovator drug to a bioequivalent generic product, or switching from one generic product to another).2 Currently, the Food and Drug Administration (FDA) requires specific pharmacokinetic ranges of generic formulations to fall within 80–125% of those of the innovator drug. Generic formulations, however, are not required to be tested against other generic formulations. As a result, neither the degree of difference that exists among generic formulations nor the clinical relevance of these differences is known. According to federal regulations for the dispensing of generic products, if a prescriber orders a drug product by generic name, the choice of manufacturer is left to the pharmacist. It has long been the practice to verify with both patient and prescriber the desire to switch from brand to generic formulations, primarily when drugs have a narrow therapeutic range or require either laboratory tests or serum drug level monitoring. It is not, however, common to inquire or verify which manufacturer’s product should to be used when dispensing generic medications.

T-Cell Receptor-Stimulated Calcineurin Activity Is Inhibited in Isolated T Cells from Transplant Patients

The addition of calcineurin inhibitors, including cyclosporine A (CsA) and FK-506 (tacrolimus), to transplant protocols has markedly reduced acute allograft rejection and prolonged patient survival. Although monitoring of serum drug levels has been shown to be a poor indicator of efficacy, there is little data on calcineurin enzymatic activity in humans. Therefore, we measured calcineurin in isolated CD3(+)/4(+) T cells from 81 non-transplant controls and 39 renal allograft patients by using a (32)PO(4)-labeled calcineurin-specific substrate. A gender difference was observed in the control cohort, with activity in males significantly higher than that in females (1073 +/- 134 versus 758 +/- 75 fmol/microg/min, respectively). Activity of both groups was comparably inhibited by 5 ng/ml tacrolimus (27 +/- 4 versus 30 +/- 4%). Calcineurin is a downstream target of the T-cell receptor (TCR). Therefore, activity was measured in isolated T cells after incubation with anti-CD3/CD28 antibodies to stimulate the TCR. Calcineurin activity increased significantly from 1214 +/- 111 to 1652 +/- 138 fmol/microg/min; addition of either tacrolimus or CsA (500 ng/ml) blocked CD3/CD28 stimulation. Despite therapeutic levels of tacrolimus and CsA (mean 11.4 and 172 ng/ml), basal calcineurin activity was significantly higher among renal transplant recipients than controls (1776 +/- 175 versus 914 +/- 78 fmol/microg/min). In contrast, anti-CD3/CD28 antibodies failed to stimulate calcineurin activity in transplant subjects. Finally, we found that basal and stimulated calcineurin activities are inversely related. Consistent with this finding, basal activity in resting T cells rose over time after transplant but stimulation fell (r(2) = 0.785, p < 0.05). These data suggest that examination of TCR-stimulated calcineurin activity after renal transplantation may be useful for monitoring immunosuppression of individual patients.

Managing drug interactions in the patient with aspergillosis.

Drug interactions are a common and recurring problem in immunocompromised patients with aspergillosis. While the introduction of new antifungals has expanded opportunities for lowering drug toxicity, virtually all antifungal regimens still carry the risk for pharmacokinetic and pharmacodynamic interactions. Drug interactions affecting the pharmacokinetics of antifungals used in the treatment of aspergillosis, or interactions that decrease the metabolism/elimination of a drug with a narrow index for efficacy (e.g. anti-retroviral therapy) or safety (e.g. immunosuppressants, chemotherapy) have the greatest potential to cause serious harm. Additionally, azole-based treatment regimens for aspergillosis carry a risk for uncommon, but potentially life-threatening, interactions that affect cardiac conduction leading to severe tachyarrythmias such as Torsades des Pointes. Clinical diagnosis of antifungal drug interactions in immunocompromised patients remains a challenge, as adverse sequelae are often masked by infection or other drug therapies (especially chemotherapy). Therefore, a high index of suspicion and a proactive, multidisciplinary approach is essential for preventing drug interactions in patients with aspergillosis. Improvements in laboratory support (i.e. patient pharmacogenetic profiling, expanded use of serum drug level monitoring) will become increasingly important for managing drug interactions patients on complex treatment regimens.

A retrospective drug utilization evaluation of vancomycin usage in paediatric patients.

To evaluate the appropriateness of use of vancomycin in paediatric patients at KK Women's and Children's Hospital, the major paediatric hospital in Singapore to identify potential problems in prescribing practices that may necessitate intervention to optimize vancomycin usage. A retrospective drug utilization evaluation was performed for paediatric patients who received intravenous vancomycin from 1 June 1998 to 31 June 1999. The outcome measures were consistency of vancomycin indication with recommended guidelines, dosing regimens, microbiological data, monitoring of serum drug levels, renal function, clinical outcomes and adverse drug reactions (ADRs). A total of 96 cases was available for evaluation. Sixty-two (64.6%) courses of vancomycin were consistent with guidelines for indication of therapy. Eighty-six (89.6%) of the dosing regimen were consistent. All infusion times that were recorded (56.3%) were consistent with criteria. Of the patients treated with vancomycin for more than 1 day, peak and/or trough serum vancomycin levels were ordered for 70 cases. Of the 56 cases with paired levels ordered, 46 cases had at least one level that fell outside the therapeutic range. Nineteen (19.8%) cases of ADRs were documented. Fifty-eight (60.4%) cases received concurrent nephrotoxic drugs. However, a substantial portion of vancomycin courses were apparently not prescribed for appropriate indications, and there was poor recording of vancomycin administration information and sampling time. The majority of dosing regimens of vancomycin was consistent with guideline criteria. The most evident problem was the sub-optimal use of the monitoring of vancomycin serum levels. The information derived from this study may be used as a for further study and for the development of strategies for optimize vancomycin usage.

Medications in pregnancy and lactation

Lack of information and misinformation often lead to physicians advising mothers to discontinue breastfeeding because of medication use. Also, many mothers do not adhere to their prescriptions or quit breastfeeding because of medication use. Although in both cases this cessation of breastfeeding is probably based on concern for the infant's safety, the physician may also be influenced by expediency and fear of litigation. The safest course for physicians who are treating nursing mothers is to consult reliable sources before advising discontinuation of breastfeeding. Overwhelming evidence has shown that breastfeeding is the most healthful form of nutrition for babies and should therefore be encouraged by physicians. Physicians should take the following approach to maximize safe maternal medication use for both the mother and the breastfed infant: 1. Determine if medication is necessary. 2. Choose the safest drug available, that is, one that; is safe when administered directly to infants, has a low milk:plasma ratio, has a short half-life, has a high molecular weight, has high protein binding in maternal serum, is ionized in maternal plasma, is less lipophilic. 3. Consultation with the infant's pediatrician is encouraged. 4. Advise the mother to take the medication just after she has breastfed the infant or just before the infant's longest sleep period. 5. If there is a possibility that a drug may risk the health of the infant, arrange for the monitoring of serum drug levels in the infant. Emergency physicians are often faced with the daunting task of treating a large variety of high-acuity patients, including patients who happen to be pregnant or nursing mothers. Priority, of course, needs to be given to life-saving treatment. When physicians are treating pregnant or breastfeeding patients, they need to use reliable resources to evaluate the risks and benefits of the medication for the mother and the infant. Most medications should have no effect on milk supply or on infant well-being. In most cases, treatment plans for patients should include encouragement from the emergency physician that he or she has researched the chosen medicine and that breastfeeding may safely continue.

ＴＤｘ‐ジベカシンキットを用いた蛍光偏光免疫測定法（ＦＰＩＡ）による硫酸アルベカシンの血中濃度測定の評価

The two methods of high performance liquid chromatography (HPLC) and bioassay have been reproted for determining arbekacin sulfate (ABK) in serum. The former method is inappropriate for clinical use due to inconvenient sample preparation, and the latter is insufficient because of its long assay time or influence of concomitant antibiotics. Therefore, the “TDx dibekacin kit” (TDx-DBK) for determination of serum arbekacin was used and evaluated in an effort to develop a practical method.The calibration curve obtained demonstrated a good correlation (r=0.9993): the regression equation was Y=0.75X+ 1.15 within the 0-10μg/ml range. The coefficient of variation of within-run precision for five concentrations of arbekacin in serum (0.5, 1.0, 2.5, 5.0, 10. 0μg/ml) was less than 5% and that of between-run precision for three concentrations (1.0, 5.0, 10.0 μg/ml) was lesst han 7%.The serum ABK (24 samples) concentrations were determined using this method and compared with those determined by HPLC. Good agreement was noted between the results derived by this TDx-DBK method and those by HPLC, where the correlation coefficient was more than 0.957. These results indicate that this TDx-DBK method may be useful for serum drug-level monitoring of patients undergoing ABK therapy.

Serum drug level monitoring in affective disorders.

This study surveyed serum level monitoring of lithium and carbamazepine in three psychiatric hospitals, to determine how the service is used with respect to affective disorders. The monitoring of lithium serum levels appears to be carried out in relatively close adherence to recommended guidelines. Carbamazepine serum levels are monitored with a similar frequency to lithium, despite the lack of an established therapeutic window for indications other than epilepsy. Changes in drug therapy, which are consequent upon monitoring of serum drug levels, occurred after only 7.5% of lithium and 13.7% of carbamazepine samples. Changes were made independently of serum level results with greater frequency in carbamazepine-treated patients, although less frequently with lithium-treated patients. Adverse consequences of such changes occurred only once, involving lithium. More research is needed to determine the potential benefits of carbamazepine serum level monitoring in affective disorders because the service appears to be overutilized at present.

The Utility of Serum Drug Level Monitoring During Therapy with Class III Antiarrhythmic Agents

Serum drug level monitoring facilitates dosage optimization of agents with a narrow therapeutic index. Concentration-dependent antiarrhythmic and toxic effects have been demonstrated for several class I drugs, whereas the concentration-effect relationships of class III antiarrhythmics are less well established. The efficacy and toxicity of amiodarone, in particular, may be determined more by extensive tissue deposition than by its serum concentration. Furthermore, accumulation of the active metabolite desethylamiodarone seems to play an additional role. The antiarrhythmic serum concentration range of sotalol is wide; monitoring is not required. The clinical utility of serum concentration measurements with the newly developed class III antiarrhythmic agents remains to be evaluated in properly planned therapeutic trials in patients with supraventricular and ventricular arrhythmias.

血清中ジコキシン濃度測定のためのＥｎｚｙｍｅ Ｉｍｍｕｎｏｍｅｔｒｉｃ Ａｓｓａｙの評価

Enzyme immunometric assay (EIMA method) for determination of serum digoxin concentration was evaluated. The coefficient of variation of within-run and between-run precision for 3 concentrations of digoxin in serum (0.85, 1.5, 3.0ng/ml) was less than 6.0%.The serum digoxin (47 samples) concentrations were determined by EIMA method and compared with those determined by fluorescence polarization immunoassay (FPIA method).There were good agreement between results by FPIA method and those by EIMA method, where correlation coefficient was more than 0.993.The cross-reactivities of methyldigoxin, lanatoside C, digoxigenin, digitoxin, proscillaridin and k-strophanthin at 2 ng/ml were found.No clinically significant interference was observed with endogenous substances at concentrations below 415 mg/dl hemoglobin, 400mg/dl cholesterol, 500mg/dl triglycerides and 10mg/dl bilirubin.The digoxin-like substances in plasma of renal insufficient patients caused minimal interference.From these results, EIMA method may be useful for serum drug-level monitoring of patients under the digoxin therapy.

Management of headaches

Migraine headaches can be successfully treated both abortively and prophylactically with carefully selected pharmaceutical agents. Mixed headache syndrome is complex and difficult to manage. Treatment is often complicated by patients' susceptibility to dependency and accompanying sleep disturbances, as well as by troublesome drug interactions. Cranial neuralgias can be successfully treated in the majority of cases. Since many patients with cranial neuralgias are elderly, careful monitoring of serum drug levels and frequent blood cell counts during therapy are crucial.

A Double-blind Placebo Controlled Study of Desipramine in the Treatment of ADD: II. Serum Drug Levels and Cardiovascular Findings

In a 6-week study of children and adolescents with attention deficit disorder with hyperactivity (ADDH) in which desipramine (DMI) was highly effective and well tolerated, the mean maximal daily oral dose in the DMI-treated patients (N = 31) was 4.6 ± 0.2 mg/kg. Additional data were obtained for 27 placebo nonresponders given DMI openly for 6 additional weeks following a nearly identical protocol and mean daily doses (total N = 58). Individual serum drug concentration varied widely at a given dose. The overall median serum DMI level was 152 ng/ml and in 6 of 56 cases with assayed serum (DMI), the level exceeded 500 ng/ml. Serum tended to be higher with older age and greater clinical improvement. Only small, clinically unimportant but statistically significant increases in diastolic blood pressure, heart rate, and electrocardiographic conduction parameters occurred. DMI-treated patients showed higher incidence during DMI treatment of sinus tachycardia and ECG evidence of intraventricular conduction defect (IVCD) of the right bundle branch block type, with two of these patients developing complete IVCD. Increases in ventricular rate and in ECG conduction parameters, as well as the incidence of IVCD, were higher in patients attaining serum levels of DMI above the median. These findings suggest that, although treatment with DMI at daily doses above 3.5 mg/kg may be needed in some cases of childhood ADDH, such doses require caution and monitoring of serum drug levels and ECG when they are used in the pediatric population.

Mechanisms of aminoglycoside nephrotoxicity.

Aminoglycosides continue to be widely used for the treatment of serious Gram-negative infections. Ten to fifteen per cent of all courses of therapy are complicated by declines in renal function, despite close monitoring of serum drug levels. The proposed pathogenesis and biochemical mechanisms of renal dysfunction caused by these commonly used therapeutic agents are discussed.