Assessment of the Effects of a High Amikacin Dose on Plasma Peak Concentration in Critically Ill Children.

OBJECTIVES: This study aimed to assess the incidence of amikacin plasma peak concentration (Cmax) below 60 mg·L-1 in critically ill children receiving an amikacin dosing regimen of 30 mg kg-1·day-1. Secondary objectives were to identify factors associated with low Cmax and to assess the incidence of acute kidney injury (AKI). METHODS: A retrospective observational study was performed in two French pediatric intensive care units. All admitted children who received 30 mg·kg-1 amikacin and had a Cmax measurement were eligible. Clinical and biological data, amikacin dose, and concentrations were collected. RESULTS: In total, 30 patients were included, aged from 3 weeks to 7 years. They received a median amikacin dosage of 30 mg kg-1·day-1 (range 29-33) based on admission body weight (BW), corresponding to 27 mg kg-1·day-1 (range 24-30) based on actual BW. Cmax was < 60 mg·L-1 in 21 (70%) children and none had a Cmax ≥ 80 mg·L-1. Among the 15 patients with a measured minimum inhibitory concentration (MIC), 13 (87%) had a Cmax/MIC ratio > 8. Univariate analysis showed that factors associated with Cmax < 60 mg·L-1 were high estimated glomerular filtration rate (p = 0.015) and low blood urea concentration (p = 0.001). AKI progression or occurrence was observed after amikacin administration in two (7%) and six (21%) patients, respectively. CONCLUSIONS: Despite the administration of the maximal recommended amikacin dose, Cmax was below the pharmacokinetic target in 70% of our pediatric population. Further studies are needed to develop a pharmacokinetic model in a population of critically ill children to optimize target attainment.

Impact of amikacin pharmacokinetic/pharmacodynamic index on treatment response in critically ill patients.

OBJECTIVES: This study evaluated the association between the pharmacokinetic/pharmacodynamic index and treatment response to amikacin in critically ill patients. METHODS: An observational prospective study was designed. Critically ill adult patients with infection due to amikacin-sensitive Gram-negative bacteria treated with amikacin were included. Amikacin maximum (Cmax) and minimum (Cmin) plasma concentration samples were taken during the first 48-96h after the beginning of treatment. The impact of Cmax/MIC ratio and area under the concentration-time curve (AUC)/MIC ratio on early and final clinical response, microbiological eradication, development of resistant strains and renal toxicity was analysed using a multivariate model. RESULTS: A total of 85 patients received amikacin treatment, of whom 71 (83.5%) achieved a Cmax/MIC >6, 66 (77.6%) a Cmax/MIC >8, 64 (75.3%) a Cmax/MIC >10 and 72 (84.7%) an AUC/MIC >65. Clinical response at the end of treatment was significantly greater in patients with Cmax/MIC >6 [OR=5.48 (95% CI 1.28-11.40)], Cmax/MIC >8 [OR=6.01 (2.41-12.2)] and Cmax/MIC >10 [OR=8.02 (2.21-14.2)]. Cmax/MIC >10 was associated with a non-significant increase in microbiological eradication [OR=2.84 (0.76-10.61)]. Achieving Cmax/MIC >6 was associated with a lower proportion of patients with selection of resistant strains or with an increase in amikacin MIC (27.8% vs. 10.2%). Amikacin AUC was associated with development of nephrotoxicity [ROC curve 0.77 (0.66-0.87)]. CONCLUSIONS: The Cmax/MIC ratio of amikacin in critically ill patients is directly related to the response to treatment and the selection of resistant strains.

A prospective, controlled, randomized, non-blind, comparative study of the efficacy and safety of a once daily high dose of ceftriaxone plus ciprofloxacin versus thrice daily ceftazidime plus amikacin in empirical therapy for febrile neutropenic patients.

BACKGROUND: Empirical antibiotic treatment for febrile neutropenia is well established. The best regimen is still controversial. The purpose of this study was to evaluate the efficacy, safety, and cost of a once daily high dose of ceftriaxone plus ciprofloxacin versus thrice daily ceftazidime plus amikacin in neutropenic febrile patients. METHODS: Ninety-five patients with febrile neutropenia were included in a prospective, controlled, randomized, non-blind, comparative study. Patients were randomly assigned to one of the treatment groups (63 to the ceftriaxone/ciprofloxacin group and 32 to the ceftazidime/amikacin group) and evaluated as successes or failures according to defined criteria. Daily assessments were made of all patients and all adverse events were recorded. RESULTS: The overall incidence of documented infections was 45.9%: 24/47 (51.1%) in the ceftriaxone/ciprofloxacin group and 10/27 (37%) in the ceftazidime/amikacin group. There was a significant difference in clinical efficacy between the groups (p=0.011) at the end of therapy. The ceftriaxone/ciprofloxacin group had an overall incidence of resolution and improvement of 95.7% in comparison to 75% in the ceftazidime/amikacin group. Thirty-nine organisms were isolated, 26 (66.67%) gram-negative and 13 (33.33%) gram-positive. There was a low incidence of adverse events in both groups. CONCLUSION: The combination of a single, high dose of ceftriaxone plus ciprofloxacin daily was more effective than the standard combination of thrice daily ceftazidime plus amikacin with no significant adverse events in either group.

Early hospital discharge versus continued hospitalization in febrile pediatric cancer patients with prolonged neutropenia: A randomized, prospective study.

BACKGROUND: Hospitalization with single or multi-agent antibiotic therapy has been the standard of care for treatment of febrile neutropenia in cancer patients. We hypothesized that an empiric antibiotic regimen that is effective and that can be administered once-daily will allow for improved hospital utilization by early transition to outpatient care. PROCEDURE: Febrile pediatric cancer patients with anticipated prolonged neutropenia were randomized between a regimen of once-daily ceftriaxone plus amikacin (C + A) and imipenem monotherapy (control). Afebrile patients on C + A satisfying "Early Discharge Criteria" at 72 hr continued treatment as outpatients. We compared the outcome, adverse events, duration of hospitalization, and cost between both groups. RESULTS: A prospective randomized controlled clinical trial was conducted on 129 febrile episodes in pediatric cancer patients with prolonged neutropenia. No adverse events were seen in 32 children (84% of study arm) treated on an outpatient basis. We found a statistically significant difference between the duration of hospitalization of the C + A group [median 5 days] and control [median 9 days](P < 0.001), per episode antibiotic cost (P < 0.001) and total episode cost (P < 0.001). There was no statistically significant difference in the response to treatment at 72 hr or after necessary antimicrobial modifications. CONCLUSIONS: We conclude that pediatric febrile cancer patients initially considered at risk for sepsis due to prolonged neutropenia can be re-evaluated at 72 hr for outpatient therapy. The convenience, low incidence of adverse effects, and cost benefit of the once-daily regimen of C + A may be particularly useful to reduce the overall treatment costs and duration of hospitalization.

Economic impact of standard antibiotic therapy combined with amikacin, in clinical unit, Lodz, poland--part I.

The study "Alexander" on bacterial resistance to antibiotics conducted in Poland revealed high sensitivity of bacterial strains to simple and cheap antibiotics. In Poland pharmacoeconomic studies on the safety, effectiveness and costs of treatment are rare. Development of therapeutic standards in bacterial infections on the basis of pharmacoeconomic analyses and clinical studies determining effectiveness and safety of therapy allows for more rational pharmacotherapy. The following problems were investigated: is the treatment of serious bacterial infections with cheap standard antibiotics [SAT] or other antibiotics therapy [OAT] combined with amikacin safe and effective? What are the direct costs? How can reduction in costs be achieved? Prospective, randomized, single-blind study was performed in the group of 152 patients, admitted from 1 January to 31 July 2000, treated with amikacin combined with aminopenicillin/amoxicillin [SAT] versus other antibiotic therapy [OAT]. The economic evaluation was done by estimation of direct cost of treatment in patients with risk factors of nephrotoxicity [NT] and therapeutic drug monitoring [TDM] versus without TDM. The statistical significance was evaluated. This study revealed that effectiveness of the SAT versus OAT combined with amikacin in serious infections is high, 80% vs. 87%, respectively. Amikacin used in high once daily dose [HODD] in combined therapy with SAT or OAT was more safe in patients with risk of nephrotoxicity and TDM (21%) vs without TDM (10%) than used in conventional therapy [CT] 40% vs 19% [p < 05]. Evaluation of the absolute risk of nephrotoxicity increase in patients with TDM was 0.16 vs 0.34 Absolute Risk Increase (ARI) 0.18, Relative Risk Reduction (RRR): 0.53; 95% Confidence Interval (Cl): 0.87-2.82. The number needed to tread (NNT): 5.43; reduction of the risk of nephrotoxicity in patients without TDM treated with HODD was 0.19 vs 0.09, Absolute Risk Reduction (ARR): 0.09; RRR: 0.47; 95% CI: 0.74-1.34; NNT: 11.1; reduction of the risk of nephrotoxicity in patients with TDM treated with amikacin HODD was 0.21 vs 0.40, ARR: 0.19; RRR: 0.48; 95% CI 0.68-1.74; NNT: 5.3; Direct costs of the treatment with SAT vs OAT combined with amikacin are low [EU 78.30 vs EU 145.16] in the Clinical Unit of Lodz, compared with other countries. Out of EU 530 for the hospitalization of one patient, 86% constituted "hotel costs". Omitting TDM in patients without risk factors can significantly decrease costs by EU 66 860 per 1000 patients. Introduction of safe and cheap standard in the treatment of bacterial infections in clinical unit, shortening hospitalization by 5 days and limiting the number of patients requiring TDM service allows for a decrease in direct cost of about EU 235410 per 1000 patients/year.

Economic impact of standard antibiotic therapy combined with amikacin, in clinical unit, Lodz, Poland--part II.

The study "Alexander" on bacterial resistance to antibiotics conducted in Poland revealed high sensitivity of bacterial strains to simple and cheap antibiotics. In Poland pharmacoeconomic studies on the safety, effectiveness and costs of treatment are rare. Development of therapeutic standards in bacterial infections on the basis of pharmacoeconomic analyses and clinical studies determining effectiveness and safety of therapy allows for more rational pharmacotherapy. The following problems were investigated: is the treatment of serious bacterial infections with cheap standard antibiotics [SAT] or other antibiotics therapy [OAT] combined with amikacin safe and effective? What are the direct costs? How can reduction in costs be achieved? Prospective, randomized, single-blind study was performed in the group of 152 patients, admitted from 1 January to 31 July 2000, treated with amikacin combined with aminopenicillin/amoxicillin [SAT] versus other antibiotic therapy [OAT]. The economic evaluation was done by estimation of direct cost of treatment in patients with risk factors of nephrotoxicity [NT] and therapeutic drug monitoring [TDM] versus without TDM. The statistical significance was evaluated. This study revealed that effectiveness of the SAT versus OAT combined with amikacin in serious infections is high, 80% vs. 87%, respectively. Amikacin used in high once daily dose [HODD] in combined therapy with SAT or OAT was more safe in patients with risk of nephrotoxicity and TDM (21%) vs without TDM (10%) than used in conventional therapy [CT] 40% vs 19% [p < 05]. Evaluation of the absolute risk of nephrotoxicity increase in patients with TDM was 0.16 vs 0.34 Absolute Risk Increase (ARI) 0.18, Relative Risk Reduction (RRR): 0.53; 95% Confidence Interval (CI): 0.87-2.82. The number needed to tread (NNT): 5.43; reduction of the risk of nephrotoxicity in patients without TDM treated with HODD was 0.19 vs 0.09, Absolute Risk Reduction (ARR): 0.09; RRR: 0.47; 95% CI: 0.74-1.34; NNT: 11.1; reduction of the risk of nephrotoxicity in patients with TDM treated with amikacin HODD was 0.21 vs 0.40, ARR: 0.19; RRR: 0.48; 95% CI: 0.68-1.74; NNT: 5.3; Direct costs of the treatment with SAT vs OAT combined with amikacin are low [EU 78.30 vs EU 145.16] in the Clinical Unit of Lodz, compared with other countries. Out of EU 530 for the hospitalization of one patient, 86% constituted "hotel costs". Omitting TDM in patients without risk factors can significantly decrease costs by EU 66 860 per 1000 patients. Introduction of safe and cheap standard in the treatment of bacterial infections in clinical unit, shortening hospitalization by 5 days and limiting the number of patients requiring TDM service allows for a decrease in direct cost of about EU 235410 per 1000 patients/year.

Single-daily ceftriaxone plus amikacin versus thrice-daily ceftazidime plus amikacin as empirical treatment of febrile neutropenia in children with cancer.

OBJECTIVE: Empirical antibiotic treatment for febrile neutropenic patients has been the mainstay of treatment for many years. Beta-lactam antibiotics and aminoglycosides have been the most frequently used drug combination. The purpose of this study was to evaluate the efficacy, safety, tolerance and costs of single-daily ceftriaxone plus amikacin versus thrice-daily dose of ceftazidime plus amikacin. METHODOLOGY: One hundred and ninety-one episodes of fever and neutropenia in 128 patients from October 1997 to December 1998 were included in a prospective, open-label, single-centre study. Patients were randomly assigned to either treatment group and evaluated as successes or failures according to defined criteria. Daily assessments were made on all patients and all adverse events recorded. Univariate and multivariate analysis of outcomes and a cost analysis were carried out. RESULTS: There were 176 evaluable patient-episodes with 51.1% in the single-daily ceftriaxone-amikacin group and 48.9% in the ceftazidime-amikacin group. There were 50 positive blood cultures: 12 Gram-positive bacteria, 33 Gram-negative bacteria and five fungi. Pseudomonas aeruginosa (P. aeruginosa) accounted for 14% of total isolates. The overall success rate was 55.5% in the ceftriaxone group compared to 51.2% in the ceftazidime group (P = 0.56). Mean time to defervescence was 4.2 days in the single-daily group and 4.3 days in the thrice-daily group. There were nine infection-related deaths; five in the single-daily ceftriaxone group. The daily cost of the once-daily regime was 42 Malaysian Ringgit less than the thrice-daily regime. There was a low incidence of adverse effects in both groups, although ototoxicity was not evaluable. CONCLUSIONS: The once-daily regime of ceftriaxone plus amikacin was as effective as the 'standard' combination of thrice-daily ceftazidime and amikacin with no significant adverse effects in either group. The convenience and substantial cost benefit of the once-daily regime will be particularly useful in developing countries with limited health resources and in centres with a low prevalence of P. aeruginosa.

[Objective audiologic assessment of children treated with amikacin]. / Amikacinnal kezelt gyermekek objektív audiológiai vizsgálata.

Hearing assessment of 14 children suffered from urinary tract infection and treated by amikacin is reported. The dosage of amikacin was 7.5 mg/kg/daily for 10 days and the serum level of amikacin not exceeded the 35 mcg/ml. The aim of the study was on the one hand to determine the hearing damaging side effect of amikacin and on the other to assess the usefulness of objective methods for detection of hearing loss in this population. Authors used for screening a transient otoacoustic emission (TEOAE) during and after (2-4 weeks) therapy. If subjective and objective (TEOAE) methods gave a good result, no further checkup has considered as necessary, but if there were no evoked emission, acoustic brainstem response audiometry has been carried out for verification. It result no hearing loss could be detected in the measured specimen. In conclusion it has been stated that by proper dosage and serum level screening amikacin may no lead to hearing loss in children, and objective methods are valuable for hearing screening and monitoring of such population of children.

Once daily ceftriaxone plus amikacin vs. three times daily ceftazidime plus amikacin for treatment of febrile neutropenic children with cancer. Writing Committee for the International Collaboration on Antimicrobial Treatment of Febrile Neutropenia in Children.

BACKGROUND: The combination of ceftazidime plus aminoglycoside is widely used for the treatment of febrile neutropenic patients but requires multiple daily administration. Because the frequency of Pseudomonas aeruginosa is low in many centers, there is a rationale to test other antibiotic regimens that provide appropriate antibacterial coverage with the advantage of reduced dosing frequency, such as once daily ceftriaxone plus amikacin. METHODS: Febrile neutropenic children with leukemia, lymphoma or solid tumors after chemotherapy were included in an open, prospective, randomized, multinational study comparing once daily ceftriaxone plus amikacin vs. 8-hourly ceftazidime and amikacin. The response to antimicrobial therapy was defined as complete response, improvement or failure. Assessment of adverse events was supplemented by specific definitions of nephrotoxicity, ototoxicity, hepatotoxicity and hypokalemia. Costs were estimated from published values of acquisition costs, delivery costs and hospitalization costs. RESULTS: Efficacy was evaluable in 364 of 468 episodes in 265 children. Response rates in ceftriaxone and amikacin vs. ceftazidime and amikacin-treated episodes were 119 of 181 (66%) vs. 121 of 183 (66%), 7 of 181 (4%) vs. 9 of 183 (5%) and 55 of 181 (30%) vs. 53 of 181 (29%) for complete response, improvement and failure, respectively. Safety profiles were similar with both treatment regimens. The acquisition and administration costs were lower for the ceftriaxone and amikacin regimen. CONCLUSIONS: A once daily regimen of ceftriaxone and amikacin is as safe and clinically effective as that of three times daily ceftazidime and amikacin for the treatment of febrile neutropenic children with cancer and is more cost-effective. The once daily regimen of ceftriaxone and amikacin is suitable for outpatient treatment.

Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity.

Neonates, especially preterms, are known to have low glomerular filtration rates (GFR). This may result in elevated trough concentrations during multiple administration of aminoglycosides (AGs), potentially leading to nephro- and ototoxic reactions. The once-daily administration (q.d.) of AGs has been shown to be equally or better tolerated in adults and children than the conventional schedules (twice daily, b.i.d.; thrice daily, t.i.d.), while offering potential pharmacodynamic and nursing advantages. No data, however, are available for neonates. As a consequence, this pilot study was conducted in order to assess the tolerance of the once-a-day administration of amikacin in comparison with the twice daily dose regimen, in relation to the pharmacokinetics of the drug under these two schedules. 22 Male neonates (gestational age > or = 34 weeks; postnatal age < or = 2 days) were randomized to receive amikacin (AK) (15 mg/kg/day) q.d. (n = 10) or b.i.d. (n = 12) together with ampicillin (50 mg/kg/12 h). AK plasma levels were measured at days 1, 3, 5 and 7 of treatment just before the next dose (trough level) and 1 h after completion of infusion (peak level) and after 3 and 6 h only at day 1. Due to the small size of the samples, no difference in efficacy could be assessed and was not the aim per se. Glomerular dysfunction was assessed by creatinine clearance, and tubular injuries by the urinary excretion of proteins (retinol binding protein, beta 2-microglobulin, clara cell protein (P1) and microalbumin), enzymes (N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, alanine aminopeptidase, and gamma-glutamyltransferase), and total phospholipids (TPL) in urine. Ototoxicity was assessed by brainstem auditory evoked potentials (BAEPs) at days 0, 3 and 9 of therapy. Eight healthy neonates served as controls. All patients showed a normal and similar increase of GFR during the first postnatal days. Proteinuria did not increase, but enzymuria and TPL increased significantly during the treatment in both AK groups without significant difference between groups. BAEPs at day 9 were not significantly different between treated and untreated patients. We conclude from this pilot study that, in the absence of more toxicity, the q.d. administration of AK in neonates of > or = 34 weeks of gestational age may be recommended over its bid schedule in view of its potential advantages.

[Assessment of the nephrotoxicity of amikacin in patients with cystic fibrosis]. / Untersuchung der Nephrotoxizität von Amikacin bei Patienten mit zystischer Fibrose.

Cystic fibrosis patients are at risk for nephrotoxic effects of aminoglycosides. Fifteen cystic fibrosis patients were admitted to hospital with 18 acute exacerbations of pulmonary symptoms associated with the isolation of Pseudomonas aeruginosa from sputum. They were treated intravenously with amikacin and ceftazidime for 14 days. Urinary excretion of N-acetyl-beta-D-glucosaminidase and alpha 1-microglobulin, two markers of tubular damage, and of albumin, a marker of glomerular permeability, was studied before and during treatment. Urinary activity of N-acetyl-beta-D-glucosaminidase and excretion of alpha 1-microglobulin was normal before amikacin treatment in approximately two thirds of patients and pathologically increased at the end of the study in 95%. Urinary albumin excretion was always normal before amikacin treatment and failed to increase consistently during treatment. The pattern of urinary protein excretion observed in the study before and during treatment with amikacin indicates a selective tubular toxicity.

Clinical pharmacokinetics, toxicity and cost effectiveness analysis of aminoglycosides and aminoglycoside dosing services.

This article reviews the clinical pharmacokinetics, clinical toxicity and cost-effectiveness analysis of aminoglycosides and of dosing services for aminoglycosides. The reader is referred elsewhere for a review of the pharmacology, antimicrobial spectrum of activity and clinical use of these drugs. A critique of the more commonly used methods of aminoglycoside dosage determinations is included, based on the inter-individual variation in aminoglycoside disposition parameters. The advantages and disadvantages of arbitrary, predictive, and pharmacokinetic methods of dosing determination are summarized. Justification for the routine determination of serum aminoglycoside concentrations is reviewed. We review the lack of standardization of definitions for aminoglycoside-associated nephrotoxicity in published studies, and studies which illustrate these differences are highlighted. Evidence for the association between serum aminoglycoside concentrations and nephrotoxicity is examined. Ototoxicity is similarly reviewed. The concept of cost-effectiveness analysis is examined extensively in this review. We discuss the literature concerning the cost benefit analysis of drug dosing services.

Impact of aminoglycoside serum assays on clinical decisions and renal toxicity.

To determine whether serum aminoglycoside assays aided clinicians in treating infections and avoiding aminoglycoside nephrotoxicity, we reviewed the charts of patients treated with aminoglycoside antibiotics parenterally. We compared 78 episodes of aminoglycoside-treated infections during which serum assays were done (group B) to 51 episodes without serum assays (group A). The groups of patients were comparable in age, outcome of infection, incidence of aminoglycoside nephrotoxicity, mean total dose of aminoglycosides given, and number of courses. Toxic trough levels of tobramycin (the most frequently used aminoglycoside) were seldom detected before the onset of nephrotoxicity, and peak tobramycin levels were frequently suboptimal. While 71% of decisions to increase or decrease the aminoglycoside dose after serum assays were considered appropriate, only 57% of noninterventions were appropriate. At our hospital, serum aminoglycoside assays did not help improve the outcome of infection or the incidence of nephrotoxicity. Their major clinical contribution was to alert the physician that serum concentrations were low.