In the past several decades, many antibiotic regimens have been proposed for the treatment of infections in febrile granulocytopenic patients with cancer. For the most part, aminoglycosides have played an important role, especially in the treatment of gram-negative rod bacteremia in these patients [1]. Aminoglycosides are rapidly bactericidal and show concentration-dependent killing, a feature that favors regimens that achieve high peak serum concentrations [2-4]. Concern over the toxicity induced by high serum concentrations of aminoglycoside, however, has heretofore restricted its clinical use [5]. Recently, several studies in vitro and in animal models have suggested that aminoglycosides can be given effectively and safely once daily to achieve high peak concentrations associated with maximal bacterial killing and without an increase in toxicity [6, 7]. Small clinical studies have reported equivalent clinical results and minimal or even reduced toxicity when the same total daily dose of aminoglycosides was administered in single daily doses compared with more frequent administration [6]. The convenience and potential cost-effectiveness of once daily administration of antibiotics plus concern over the cumulative toxicity associated with the use of other nephrotoxic agents (such as amphotericin B, cisplatin, vancomycin, or acyclovir) in patients with cancer prompted this study, which is the first large-scale clinical application of this concept. Amikacin was the chosen aminoglycoside because it has been used in our last five clinical trials without the development of resistance [8-12]. Also, we have reported our experience with single daily doses of amikacin in adults and children in two pilot studies [13, 14]. The pharmacokinetics and antibacterial activity of ceftriaxone make this drug attractive for combined single-dose therapy with amikacin. Ceftriaxone has a long half-life, and its spectrum of activity includes most gram-positive cocci, which are the predominant pathogens in patients with cancer and neutropenia [11, 15, 16], and gram-negative rods (with the exception of Pseudomonas species). However, Pseudomonas are now uncommonly isolated in patients with cancer and granulocytopenia, as shown in this and other studies [11, 16, 17]. Ceftazidime is traditionally administered thrice daily and has been used in combination with amikacin as the standard regimen in several of our previous studies [10, 11]. With the exception of Pseudomonas, we found that the activities of ceftriaxone and ceftazidime against 365 aerobic bacteria isolated from the blood of neutropenic patients enrolled in our previous trials were virtually superimposable. This trial compared single daily administration of amikacin and ceftriaxone with multiple daily dosing of amikacin and ceftazidime in 858 febrile episodes in granulocytopenic patients with cancer. Materials and Methods Participating Centers and Patient Eligibility The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC) consisted of 21 tertiary care or university medical centers located in Europe (n = 18), in the United States (n = 2), and in the Middle East [n = 1]. Patients with cancer were eligible for this study if they had 1) granulocytopenia [<1000 granulocytes/mm3]; 2) fever (defined as a temperature 38 C [ 100.4 F] on one occasion in the absence of an obvious noninfectious cause of fever, such as blood product, cytotoxic drug administration, or tumor fever); and 3) not received parenteral antibiotics for at least 4 days before randomization. Patients who were treated with any prophylactic antimicrobial agent were eligible for the study; however, antibacterial prophylaxis was discontinued with the institution of intravenous antibiotics. Patients could re-enter the protocol provided that they had not received antibiotics for at least 4 days and that the second randomization did not occur during the same episode of granulocytopenia, a standard practice in trials in these patients. Patients were excluded if 1) they were allergic to any of the trial antibiotics; 2) they required hemodialysis or peritoneal dialysis or had a serum creatinine concentration greater than 300 mol/L; or 3) they were pregnant or nursing. The protocol was approved by the EORTC Protocol Review Committee (EORTC study number 46882) and by the Human Subjects or Ethics Committee of each participating institution. The trial was conducted in accordance with the Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects of the Declaration of Helsinki. Written or oral informed consent was obtained, depending on the requirements of the local Ethics Committee. Randomization Procedure Patients were randomly allocated by drawing consecutive sealed envelopes to one of the following two regimens: amikacin plus ceftazidime (control regimen) or amikacin plus ceftriaxone (experimental regimen). Randomization was stratified by institution and by underlying condition (leukemia, lymphoma, or bone marrow transplantation compared with solid tumors). Therefore, two randomization lists were established for each institution (one for patients with leukemia, lymphoma, and bone marrow transplantation and one for patients with solid tumors). We used random permuted blocks of six, so that equal numbers of patients would be randomized to each trial arm with every six patients entered. Study Design, End Points, and Sample Size The specific hypothesis tested in this prospective, randomized, multicenter study was whether once daily amikacin and ceftriaxone was as effective as multiple daily amikacin and ceftazidime for the empirical therapy of febrile patients with cancer and granulocytopenia. Secondary end points included the frequency of nephrotoxicity and ototoxicity. To determine the sample size for the study we assumed that: 1) among evaluable patients the overall response rate to ceftazidime and amikacin would be 75%, as observed in previous studies by our group [10, 11]; 2) a difference in efficacy of less than 10% was necessary to conclude that both treatment groups had a similar efficacy; and 3) 85% of all randomized patients would be evaluable for response to treatment. To ensure with a probability of 90% (that is, = 0.10) that the upper 95% confidence interval (CI) (that is, = 0.05) for the true difference in response rate between the two treatment groups would not exceed 10%, 322 evaluable patients were needed in each study arm. Thus, assuming a 15% nonevaluability rate, 760 patient entries was required. Interim analysis was not done. Antibiotic Treatment The antibiotics were mixed in 50 mL of 5% dextrose in water and were sequentially infused intravenously (the -lactam was administered first). The infusion time was 15 minutes for each of the antibiotics, except for single-dose amikacin, which was infused in 60 minutes. The 60-minute infusion time for amikacin given every 24 hours was chosen because of limited experience with shorter infusion times when the study was designed. Ceftriaxone was administered once daily at a dose of 30 mg/kg in adults (the average adult received 2 g) and 80 mg/kg in children younger than 12 years. Ceftazidime was administered as 100 mg/kg per day in three divided doses. An average adult received 2 g of ceftazidime every 8 hours. Amikacin was administered as 20 mg/kg per day, given either once daily or in three divided doses. Maximal daily doses were 2 g for ceftriaxone, 6 g for ceftazidime, and 1.5 g for amikacin. Twice-weekly monitoring of the serum concentrations of amikacin was recommended. The protocol suggested that peak (30 minutes after the end of infusion) and trough (preinfusion) serum amikacin concentrations of 26 to 32 g/mL (8-hour group) and less than 10 g/mL (for both 24-hour and 8-hour groups), respectively, should be achieved. No recommendation was made for peak serum levels of once daily amikacin, because no such data were available for patients with cancer and neutropenia when the study was designed. Monitoring of the serum levels of the -lactam antibiotics was not required. The minimum duration of therapy was 7 days, except in patients with noninfectious fever, in whom treatment was discontinued after 4 days. Patient Evaluation and Classification of Febrile Episodes All patients were evaluated before and during the trial according to previously published procedures [10, 11]. Case report forms were reviewed by the Data Manager and by the Data Review Committee as previously published [11]. Primary febrile episodes were classified as 1) microbiologically documented infections with or without bacteremia; 2) clinically documented infections; 3) unexplained fever [formerly classified as possible infections]; or 4) noninfectious fever (such as fever related to transfusion of blood products, chemotherapy, or the underlying cancer) according to definitions published previously [9, 11]. Bacteria isolated from blood were sent to the Microbiological Reference Center (Clinical Microbiology Laboratory, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland), where standardized identification methods and antibiotic susceptibility tests were done [18-20]. Evaluation of susceptibility data was done using the zone diameter interpretive standards and equivalent minimum inhibitory concentration recommended by the National Committee for Clinical Laboratory Standards: Break points for resistance were an inhibitory zone diameter of 14 mm or less for ceftazidime and amikacin and of 13 mm or less for ceftriaxone or as a minimum inhibitory concentration of 32 g/mL or more for ceftazidime and amikacin and 64 g/mL or more for ceftriaxone. Evaluation of Response A patient's trial was evaluated as a success if fever and clinical signs of infection (whenever present) resolved and if the infecting microorganism [whenever isolated] was eradicated without change of the allocated antibacterial ther

Efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia

Antibacterials are the primary cause of drug-induced kidney disease in all age groups and these agents bring about renal damage by 2 main mechanisms, namely, direct and immunologically mediated. For some antibacterials (aminoglycosides and vancomycin) nephrotoxicity is very frequent but generally reversible upon discontinuation of the drug. However, the development of acute renal failure with these agents is possible and its incidence in the newborn seems to be increasing. Antibacterials are very often used in the neonatal period especially in very low birthweight neonates. The role of neonatal age in developing nephrotoxicity has still to be defined. Since the traditional laboratory parameters of nephrotoxicity are abnormal only in the presence of substantial renal damage, the identification of early non-invasive markers of the renal damage (urinary microglobulins, enzymes and growth factors) is of importance. Aminoglycosides and glycopeptides are still frequently used, either alone or in combination, despite their low therapeutic index. Numerous factors intervene in bringing about the kidney damage induced by these 2 classes of antibacterials, such as factors related to the antibacterial itself and others related to the associated pathology as well as pharmacological factors. Nephrotoxicity can be caused by the beta-lactams and related compounds. Their potential to cause nephrotoxicity decreases in the order: carbapenems > cephalosporins > penicillins > monobactams. Third generation cephalosporins are frequently used in neonates. However, they are well tolerated compounds at the renal level. The nephrotoxicity of other classes of antibacterials is not discussed either because they are only used in neonates in exceptional circumstances, for example, chloramphenicol and cotrimoxazole (trimethoprim-sulfamethoxazole) or are not associated with significant nephrotoxicity, for example macrolides, clindamicin, quinolones, rifampicin (rifampin) and metronidazole. Antibacterial-induced nephrotoxicity is an important parameter to be considered when treating the newborn and this is particularly true when use of a combination of different antibacterials and/or drugs with a nephrotoxic potential is being considered. However, other parameters, such as antibacterial spectrum, pharmacokinetics, post-antibacterial effect, clinical efficacy, general adverse effect profile and cost, must also be considered in the choice of antibacterial therapy in the neonate. Knowledge of the renal safety of antibacterials and the correct approach to therapeutic drug monitoring may be useful elements for preventing iatrogenic renal disorders.

Antibacterial-induced nephrotoxicity in the newborn.

OBJECTIVE:To provide an overview of the efficacy and adverse effects associated with once-daily administration of aminoglycosides.DATA SOURCES:An extensive MEDLINE search and review of journals was conducted to identify information for this review.DATA SYNTHESIS:Aminoglycosides alone or in combination with beta-lactams are commonly used for their activity against gram-negative microorganisms. Numerous studies have been performed comparing efficacy and toxicity of once-daily administration of aminoglycosides with multiple-daily dosing. Two studies have found a significant difference in clinical efficacy between once-daily and multiple-daily dosing of aminoglycosides. Several studies have observed a lower incidence of toxicity with once-daily than multiple-daily dosing, but others have found no difference.CONCLUSIONS:Review of the literature suggests that once-daily administration of aminoglycosides may be as safe and effective as multiple-daily dosing regimens for the treatment of certain infections caused...

Once-Daily Administration of Aminoglycosides

To evaluate the rationale behind dosing aminoglycosides as a single daily dose versus traditional dosing approaches, we conducted a MEDLINE search to identify all pertinent articles, and also reviewed the references of all articles. Single daily dosing of aminoglycosides is not a new concept, having been examined since 1974. The advantages of this regimen include optimum concentration-dependent bactericidal activity, longer dosing intervals due to the postantibiotic effect (PAE), and prevention of bacterial adaptive resistance. Because of longer dosing intervals, toxicity may also be delayed or reduced. Costs may be reduced due to decreased monitoring and administration. Clinically, the regimen has been implemented in various patient populations with reported success. Questions remain, however, about optimum dose, peak and trough serum concentrations, and dose adjustment in patients with renal impairment or neutropenia. More clinical experience with this method in large numbers of patients has to be published. Pharmacists can be instrumental in monitoring patients receiving once-daily therapy and by educating health care professionals as to the rationale behind the therapy.

Single Daily Dosing of Aminoglycosides

Pharmacokinetics of Once-Daily Gentamicin Dosing in Pediatric Patients

The efficacy and safety of a single 20 mg/kg daily dose of amikacin was studied in an open, uncontrolled trial in 56 infants and children. Most of the patients suffered from severe Gram-negative infection which had failed to respond to previous antibacterial therapy. Amikacin was given in combination with a beta-lactam antibiotic in 43 cases, with other antibiotics in five cases and monotherapy in eight cases. Pseudomonas aeruginosa was the most frequently isolated organism (27 cases). Clinical results were satisfactory in 98% of the infections treated. Two patients died, one from the infection and the other 8 weeks after therapy from unrelated causes. Amikacin serum concentrations were high during the first hour after iv infusion, low after 8 h and undetectable at 24 h. Nephrotoxicity and ototoxicity was not detected in any patient. Amikacin when used as a single daily dose in combination with a beta-lactam antibiotic was effective and safe in treating infants and children with severe Gram-negative infection.

Clinical and pharmacokinetic study of a single daily dose of amikacin in paediatric patients with severe Gram-negative infections

We introduce a new class of spatially stochastic physics and data informed deep latent models for parametric partial differential equations (PDEs) which operate through scalable variational neural processes. We achieve this by assigning probability measures to the spatial domain, which allows us to treat collocation grids probabilistically as random variables to be marginalised out. Adapting this spatial statistics view, we solve forward and inverse problems for parametric PDEs in a way that leads to the construction of Gaussian process models of solution fields. The implementation of these random grids poses a unique set of challenges for inverse physics informed deep learning frameworks and we propose a new architecture called Grid Invariant Convolutional Networks (GICNets) to overcome these challenges. We further show how to incorporate noisy data in a principled manner into our physics informed model to improve predictions for problems where data may be available but whose measurement location does not coincide with any fixed mesh or grid. The proposed method is tested on a nonlinear Poisson problem, Burgers equation, and Navier-Stokes equations, and we provide extensive numerical comparisons. We demonstrate significant computational advantages over current physics informed neural learning methods for parametric PDEs while improving the predictive capabilities and flexibility of these models.

Random Grid Neural Processes for Parametric Partial Differential Equations

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Clinical and pharmacokinetic study of a single daily dose of amikacin in paediatric patients with severe Gram-negative infections

Random Grid Neural Processes for Parametric Partial Differential Equations