Amikacin Therapy in Japanese Pediatric Patients: Narrative Review.

Children show a very wide range of physical development processes. These changes impact pharmacokinetic (PK) variability in pediatric patients. Most PK studies have been conducted on the Caucasian population. Therefore, whether current evidence of how developmental change affects PK and exposure-response relationships applies to Japanese pediatric patients remains unclear. This narrative review focuses on amikacin therapy in Japanese pediatric patients and shows the relationship between amikacin concentrations and efficacy/toxicity. Ten relevant articles were identified. Of these, nine articles were published in the 1980s. All studies reported a maximum concentration (Cmax) and minimum concentration (Cmin) of amikacin. Overall, articles reporting PK/pharmacodynamic (PD) indices and minimum inhibitory concentration (MIC) of isolated bacteria in Japanese pediatric patients is lacking, whereas all patients recovered from an infection state and showed negative cultures. Five of the included studies reported the association between Cmin and toxicity. The Cmin in three of four patients who developed toxicity was above 10 mg/L. This narrative review shows that further PK study of amikacin in Japanese pediatric patients is necessary. In particular, the pursuit of knowledge of Cmax/MIC ratio is vital. On the other hand, this review demonstrates that the optimal Cmin for Japanese pediatric patients is below 10 mg/L as a candidate concentration. However, it is noted that the number of patients who developed toxicity is very small.

Population Pharmacokinetic Study of the Suitability of Standard Dosing Regimens of Amikacin in Critically Ill Patients with Open-Abdomen and Negative-Pressure Wound Therapy.

The aim was to assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open-abdomen and negative-pressure therapy (OA/NPT). Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while being treated by OA/NPT was retrospectively included. A population pharmacokinetic (PK) modeling was performed considering the effect of 10 covariates (age, sex, total body weight [TBW], adapted body weight [ABW], body surface area [BSA], modified sepsis-related organ failure assessment [SOFA] score, vasopressor use, creatinine clearance [CLCR], fluid balance, and amount of fluids collected by the NPT over the sampling day) in patients who underwent continuous renal replacement therapy (CRRT) or did not receive CRRT. Monte Carlo simulations were employed to determine the fractional target attainment (FTA) for the PK/pharmacodynamic [PD] targets (maximum concentration of drug [Cmax]/MIC ratio of ≥8 and a ratio of the area under the concentration-time curve from 0 to 24 h [AUC0-24]/MIC of ≥75). Seventy critically ill patients treated by OA/NPT (contributing 179 concentration values) were included. Amikacin PK concentrations were best described by a two-compartment model with linear elimination and proportional residual error, with CLCR and ABW as significant covariates for volume of distribution (V) and CLCR for CL. The reported V) in non-CRRT and CRRT patients was 35.8 and 40.2 liters, respectively. In Monte Carlo simulations, ABW-adjusted doses between 25 and 35 mg/kg were needed to reach an FTA of >85% for various renal functions. Despite an increased V and a wide interindividual variability, desirable PK/PD targets may be achieved using an ABW-based loading dose of 25 to 30 mg/kg. When less susceptible pathogens are targeted, higher dosing regimens are probably needed in patients with augmented renal clearance (ARC). Further studies are needed to assess the effect of OA/NPT on the PK parameters of antimicrobial agents.

Amikacin Dosing for MDR Tuberculosis: A Systematic Review to Establish or Revise the Current Recommended Dose for Tuberculosis Treatment.

Background: Amikacin has been used for over 40 years in multidrug resistant tuberculosis (MDR-TB), but there is still debate on the right dose. The aim of this review was to search relevant pharmacokinetic (PK) and pharmacodynamic (PD) literature for the optimal dose and dosing frequency of amikacin in MDR-TB regimens trying to optimize efficacy while minimizing toxicity. Methods: A systematic review on the value of amikacin as second-line drug in the treatment of MDR-TB was performed. Results: Five articles were identified with data on PK, hollow-fiber system model for TB and or early bactericidal activity of amikacin. Despite the long period in which amikacin has been available for the treatment of MDR-TB, very little PK data is available. This highlights the need for more research. Conclusions: Maximum concentration (Cmax) of amikacin related to MIC proved to be the most important PK/PD index for efficacy. The target Cmax/MIC ratio should be 10 at site of infection. Cumulative area under the concentration-time curve (AUC) corresponding with cumulative days of treatment was associated with an increased risk of toxicity.

Higher versus standard amikacin single dose in emergency department patients with severe sepsis and septic shock: a randomised controlled trial.

Recent studies suggest that intensive care unit patients treated with amikacin frequently do not attain the desired pharmacokinetic/pharmacodynamic (PK/PD) target, i.e. peak amikacin concentration (Cpeak) to minimum inhibitory concentration (MIC) ratio of ≥8, when a single dose of 15 mg/kg is used. No data are available for patients admitted to the emergency department (ED). The aim of this prospective randomised controlled study was to determine PK/PD target attainment in ED patients presenting with severe sepsis or septic shock treated with 15 mg/kg versus 25 mg/kg amikacin. Patients were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg. Amikacin Cpeak values were determined. The primary outcome was target attainment defined as Cpeak/MIC ≥ 8 both using EUCAST susceptibility breakpoints and actually documented MICs as denominator. A total of 104 patients were included. The EUCAST-based target was attained in 76% vs. 40% of patients assigned to the 25 mg/kg vs. 15 mg/kg dose groups (P <0.0001). Target attainment using actual MICs (median of 2 mg/L, documented in 48 isolated Gram-negative pathogens) was achieved in 95% vs. 94% of patients in the 25 mg/kg vs. 15 mg/kg dose groups (P = 0.969). Risk factors associated with PK/PD target failure were identified in the multivariable analysis. At least 25 mg/kg amikacin as a single dose should be used in ED patients with severe sepsis and septic shock to attain the EUCAST-based PK/PD target. However, when using local epidemiology as denominator, 15 mg/kg appears to be sufficient. [ClinicalTrials.gov ID: NCT02365272.

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.

Reduced Chance of Hearing Loss Associated with Therapeutic Drug Monitoring of Aminoglycosides in the Treatment of Multidrug-Resistant Tuberculosis.

Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our tuberculosis center, we used therapeutic drug monitoring (TDM) targeting preset pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of tuberculosis (TB) patients treated with amikacin or kanamycin in the period from 2000 to 2012. Patients with culture-confirmed multiresistant or extensively drug-resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including maximum concentration (Cmax), Cmin, and audiometry data, were extracted from the patients' medical charts. A total of 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratios obtained from 57 patients were 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg of body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg, a correlation was found between the dose per kg of body weight during daily dosing and the extent of hearing loss in dB at 8,000 Hz. These findings suggest that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.

Efficacy and pharmacokinetics of ME1100, a novel optimized formulation of arbekacin for inhalation, compared with amikacin in a murine model of ventilator-associated pneumonia caused by Pseudomonas aeruginosa.

Background: Arbekacin is an aminoglycoside that shows strong antimicrobial activity against Gram-positive bacteria, including MRSA, as well as Pseudomonas aeruginosa . The therapeutic effectiveness of arbekacin is directly related to C max at the infection site. To maximize drug delivery to the respiratory tract and minimize the systemic toxicity, arbekacin optimized for inhalation, ME1100, is under development. In this study, we investigated the efficacy and pharmacokinetics of ME1100 in a murine model of ventilator-associated pneumonia caused by P. aeruginosa by using a customized investigational nebulizer system. Methods: The mice were treated for 5 min, once daily, with placebo, 3, 10 or 30 mg/mL ME1100 or 30 mg/mL amikacin. Results: In the survival study, the survival rate was significantly improved in the 10 and 30 mg/mL ME1100 treatment groups compared with that in the placebo group. The number of bacteria in the lungs was significantly lower in the 30 mg/mL ME1100 treatment group at 6 h after the initial treatment, compared with all other groups. In the pharmacokinetic study, the C max in the 30 mg/mL ME1100 treatment group in the epithelial lining fluid (ELF) and plasma was 31.1 and 1.2 mg/L, respectively. Furthermore, we compared the efficacy of ME1100 with that of amikacin. Although there were no significant differences in ELF and plasma concentrations between 30 mg/mL of ME1100 and 30 mg/mL of amikacin, ME1100 significantly improved the survival rate compared with amikacin. Conclusions: The results of our study demonstrated the in vivo effectiveness of ME1100 and its superiority to amikacin.

Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy.

There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 108 CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 108 to 109 CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates.

Pulmonary Deposition and Elimination of Liposomal Amikacin for Inhalation and Effect on Macrophage Function after Administration in Rats.

Pulmonary nontuberculous mycobacterial (PNTM) infections represent a treatment challenge. Liposomal amikacin for inhalation (LAI) is a novel formulation currently in development for the treatment of PNTM infections. The pulmonary deposition and elimination of LAI and its effect on macrophage function were evaluated in a series of preclinical studies in healthy rats. The pulmonary deposition of LAI was evaluated in female rats (n = 76) treated with LAI by nebulizer at 10 mg/kg of body weight per day or 90 mg/kg per day for 27 days, followed by dosing of dually labeled LAI (LAI with a lipid label plus an amikacin label) on day 28 with subsequent lung histological and amikacin analyses. In a separate study for assessment of alveolar macrophage function, rats (n = 180) received daily treatment with LAI at 90 mg/kg per day or 1.5% saline over three 30-day treatment periods followed by 30-day recovery periods; phagocytic and Saccharomyces cerevisiae (yeast) killing capabilities and inflammatory mediator release were assessed at the end of each period. LAI demonstrated equal dose-dependent deposition across all lung lobes and regions. Lipid and amikacin labels showed diffuse extracellular colocalization, followed by macrophage uptake and gradual amikacin elimination. Macrophages demonstrated accumulation of amikacin during treatment periods and nearly complete elimination during recovery periods. No evidence of an inflammatory response was seen. No differences in microsphere uptake or yeast killing were seen between LAI-treated and control macrophages. Neither LAI-treated nor control macrophages demonstrated constitutive inflammatory mediator release; however, both showed normal mediator release on lipopolysaccharide stimulation. LAI is readily taken up by macrophages in healthy rats without compromising macrophage function.

Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients.

Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0-24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0-24, and trough concentrations. The primary node for failure had two competing variables, Cmax of <67 mg/liter and AUC0-24 of <568.30 mg · h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R(2) = 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacin Cmax of ≥67 mg/liter versus 3/15 (20%) in those with a Cmax of <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacin Cmax and AUC0-24 below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model.

Impact of imipenem and amikacin pharmacokinetic/pharmacodynamic parameters on microbiological outcome of Gram-negative bacilli ventilator-associated pneumonia.

OBJECTIVES: Despite recent advances, antibiotic therapy of ventilator-associated pneumonia (VAP) in ICU patients is still challenging. We assessed the impact of imipenem and amikacin pharmacokinetic and pharmacodynamic parameters on microbiological outcome in these patients. PATIENTS AND METHODS: Patients with Gram-negative bacilli (GNB) VAP were prospectively included. Blood samples for pharmacokinetic analysis were collected after empirical administration of a combination of imipenem three times daily and one single dose of amikacin. MICs were estimated for each GNB obtained from respiratory samples. Microbiological success was defined as a ≥10(3) cfu/mL decrease in bacterial count in quantitative cultures between baseline and the third day of treatment. RESULTS: Thirty-nine patients [median (min-max) age = 60 years (28-84) and median SAPS2 at inclusion = 40 (19-73)] were included. Median MICs of imipenem and amikacin were 0.25 mg/L (0.094-16) and 2 mg/L (1-32), respectively. Median times over MIC and over 5× MIC for imipenem were 100% (8-100) and 74% (3-100), respectively. The median C1/MIC ratio for amikacin was 23 (1-76); 34 patients (87%) achieved a C1/MIC ≥10. Microbiological success occurred in 29 patients (74%). No imipenem pharmacodynamic parameter was significantly associated with the microbiological success. For amikacin, C1/MIC was significantly higher in the microbiological success group: 26 (1-76) versus 11 (3-26) (P = 0.004). CONCLUSIONS: In ICU patients with VAP, classic imipenem pharmacodynamic targets are easily reached with usual dosing regimens. In this context, for amikacin, a higher C1/MIC ratio than previously described might be necessary.

Plasma drug activity in patients on treatment for multidrug-resistant tuberculosis.

Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (C2) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a -2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the C2 values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin C2/MIC ratios than subjects with a TDA of ≥1.5 (9.8 ± 8.7 versus 27.0 ± 19.1; P = 0.04). The mean TDAs were 2.52 ± 0.76 in subjects converting to negative in ≤2 months and 1.88 ± 0.57 in subjects converting to negative in >2 months (P = 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity ex vivo. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response.

Guidelines for aminoglycoside use and applicability to geriatric patients.

OBJECTIVES: The authors had for objective to evaluate the applicability of AFSSAPS guidelines for aminoglycoside use to geriatric patients. METHODS: Theoretical doses and dosing regimens allowing reaching target concentrations in this population were calculated by applying a pharmacokinetic model to 30 geriatric patients treated by amikacin. RESULTS: The dose allowing reaching a maximum concentration of 60 mg/L was 1.217 mg on average. The time required to reach a blood concentration lower than or equal to 2.5mg/L was 62.5±70.4 hours. Forty-six percent of patients had a trough concentration greater than 2.5 mg/L, 48 hours after administration. For these patients, the time between critical minimum inhibitory concentration (MIC) and toxicity threshold concentration was 21.9±14.9 hours. CONCLUSION: Reaching a target concentration can be problematic in geriatric patients. It is frequently necessary to use dosing intervals greater than 48 hours. The effectiveness and safety of these regimens remain uncertain.

The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment.

RATIONALE: Currently recommended multidrug treatment regimens for Mycobacterium avium complex (MAC) lung disease yield limited cure rates. This results, in part, from incomplete understanding of the pharmacokinetics and pharmacodynamics of the drugs. OBJECTIVES: To study pharmacokinetics, pharmacodynamics, and drug interactions of multidrug treatment regimens in a large cohort of patients with MAC lung disease. METHODS: We retrospectively collected pharmacokinetic data of all patients treated for MAC lung disease in the Adult Care Unit at National Jewish Health, Denver, Colorado, in the January 2006 to January 2010 period; we retrospectively calculated areas under the time-concentration curve (AUC). Minimum inhibitory concentrations (MIC) of their MAC isolates were retrieved for pharmacodynamic calculations. MEASUREMENTS AND MAIN RESULTS: We included 531 pharmacokinetic analyses, performed for 481 patients (84% females; mean age, 63 yr; mean body mass index, 21.6). Peak serum concentrations (C(max)) below target range were frequent for ethambutol (48% of patients); clarithromycin (56%); and azithromycin (35%). Concurrent administration of rifampicin led to 68%, 23%, and 10% decreases in C(max) of clarithromycin, azithromycin, and moxifloxacin. C(max)/MIC or AUC/MIC ratios associated with bactericidal activity were seldom met; 57% of patients achieved target ratios for ethambutol, versus 42% for clarithromycin, 19% for amikacin, 18% for rifampicin, and 11% for moxifloxacin. CONCLUSIONS: Currently recommended regimens for MAC lung disease yield important pharmacologic interactions and low concentrations of key drugs including macrolides. Pharmacodynamic indices for rifampicin, clarithromycin, amikacin, and moxifloxacin are seldom met. This may partly explain the poor outcomes of currently recommended treatment regimens. Trials of new drugs and new dosing strategies are needed.

Resistencia antimicrobiana en aislados clínicos de Pseudomonas aeruginosa / Antimicrobial resistance in clinical patterns of Pseudomonas aeruginosa

Pseudomonas aeruginosa es un microorganismo oportunista frecuentemente implicado en infecciones de origen nosocomial que presenta resistencia natural y adquirida a muchos de los antimicrobianos de uso clínico. Se llevo a cabo un estudio de resistencias a antimicrobianos de 3.029 aislamientos de P. aeruginosa de enfermos intra y extrahospitalarios en el periodo 2005-2010. La metodología utilizada fue, el método semiautomatizado WIDER I (Soria Melguizo), para la identificación de las especies y para el estudio de sensibilidades a antimicrobianos. Se consideraron los criterios de sensibilidad y resistencia recomendados por el grupo MENSURA. En nuestro hospital existe un mantenimiento relativo de la sensibilidad antimicrobiana de P. aeruginosa en el periodo 2005-2010, con un aumento de esta en amikacina, gentamicina y cefalosporinas. Existen diferencias de porcentajes de sensibilidades entre las cepas de origen intrahospitalario y extrahospitalario, salvo para fosfomicina y tobramicina. Destacamos la importancia de realizar estudios locales de la sensibilidad y resistencias de P. aeruginosa en cada zona, de forma periódica para poder valorar las diferentes pautas terapéuticas, no siendo posible extrapolar los datos de las diferentes regiones españolas(AU)

Pseudomonas aeruginosa is an opportunistic microorganism that is frequently the cause of nosocomial infections. Multiple mechanisms are involved in its natural and acquired resistance to many of the antimicrobial agents commonly used in clinical practice. We performed an antibiotic resistance study on P. aeruginosa isolated from intrahospitalary and extrahospitalary samples between 2005 and 2010 years. We included in the study a global amount of 3,029 P. aeruginosa isolates from clinical samples received at University Hospital Reina Sofia. Microbiology Service in Córdoba (Spain). Semiautomatic system WIDER I for strains identification and sensibility testing was employed. We considered susceptibility and resistance criteria recommended by MENSURA group. Results of the analysis showed that P. aeruginosa maintanied similar levels of antimicrobial susceptibility during the period 2005-2010, with increased susceptibility to amikacin, gentamicin and cefalosporins. There were also important differences in the degree of susceptibility between intrahospital and extrahospital strains during 2010 year, except for tobramicin and fosfomycin. The intrahospital difference in susceptibility was also evaluated, emphasizing the importance of periodically surveillance of susceptibility and resistance patterns of P. aeruginosa, in each setting in order to evaluate different therapeutic guidelines, because it is not always advisable to extrapolate data from different regions(AU)

Pharmacokinetics of a loading dose of amikacin in septic patients undergoing continuous renal replacement therapy.

Data on the optimal amikacin regimen during continuous renal replacement therapy (CRRT) are scarce and the proposed loading dose of 10mg/kg may result in inadequate drug levels. The aim of this study was to describe the pharmacokinetics of a 25 mg/kg first dose of amikacin in septic shock patients treated with CRRT. Serum samples were collected before (t=0 h) and at 1 (peak), 1.5, 4.5, 8 and 24 h after a 30-min amikacin infusion in 13 consecutive patients treated with a combination of amikacin and ß-lactam. Blood amikacin levels were measured using a validated fluorescence polarisation immunoassay method. In 9 patients (69%) the peak concentration was >64 mg/L, which corresponds to eight times the minimal inhibitory concentration breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Enterobacteriaceae and Pseudomonas aeruginosa (susceptible <8 mg/L, resistant >16 mg/L). The median (range) total volume of distribution was 0.50 L/kg (0.22-4.05 L/kg), the elimination half-life was 6.5h (4.5-279.6h) and total drug clearance (CL) was 1.26 mL/min/kg (0.1-3.30 mL/min/kg). Only three patients had drug concentrations at 24h (C(min)) of <5mg/L and the median predicted time needed to reach this value was 34 h (14-76 h). There was no correlation between CRRT parameters and C(min), CL or the time to C(min)<5mg/L. In septic shock patients treated with CRRT, a first dose of ≥ 25 mg/kg amikacin is therefore required to reach therapeutic peak concentrations. However, as drug clearance is reduced, amikacin concentrations remained above the threshold of renal toxicity at 24h. The therapeutic benefit of high-dose aminoglycoside therapy should be balanced with its potential renal effects in septic patients receiving CRRT.

Pharmacokinetics of once-daily amikacin in healthy foals and therapeutic drug monitoring in hospitalized equine neonates.

The objectives of this study were to investigate the pharmacokinetics of once-daily amikacin in healthy neonates, to determine amikacin concentrations in hospitalized foals, and to determine the minimum inhibitory concentrations (MICs) of amikacin against gram-negative isolates from blood cultures in septic foals. Median half-life, clearance, and volume of distribution of amikacin in healthy 2- to 3-day-old foals after administration of an intravenous bolus of amikacin (25 mg/kg) were 5.07 hours (4.86-5.45 hours), 1.82 mL/min/kg (1.35-1.97 mL/min/kg), and 0.785 L/kg (0.638-0.862 L/kg), respectively. Statistically significant (P <.05) decreases in area under the curve (14% decrease), mean residence time (19% decrease), and C24h plasma amikacin concentrations (29% decrease) occurred between days 2-3 and 10-11. Plasma amikacin concentrations in healthy foals at 0.5 hours (C0.5h) were significantly higher (P = .02) than those of hospitalized foals. Sepsis, prematurity, and hypoxemia did not alter amikacin concentrations. The MIC at which 90% of all gram-negative isolates from equine neonatal blood cultures were inhibited by amikacin was 4 microg/mL, suggesting that amikacin C0.5h of 40 microg/mL should be targeted to achieve a maximum serum concentration to MIC ratio of 10:1. The proportion of foals with C0.5h 40 microg/mL was significantly higher (P < .0001) in hospitalized foals receiving a dose of amikacin at 25 mg/kg (22/24 or 92%) than in foals receiving a dose at 21 mg/kg (9/25 or 36%), whereas no difference was found in the proportion of foals with C24h concentrations > or = 3 microg/mL between the 2 groups. An initial dose at 25 mg/kg is recommended for once-daily amikacin in equine neonates.

n-6 polyunsaturated fatty acids enhance the activities of ceftazidime and amikacin in experimental sepsis caused by multidrug-resistant Pseudomonas aeruginosa.

Recent in vitro and ex vivo studies disclosed an enhancement of the activity of antimicrobials on multidrug-resistant Pseudomonas aeruginosa by n-6 polyunsaturated fatty acids (PUFAS); therefore their effect was evaluated in experimental sepsis in 60 rabbits. Solutions of gamma-linolenic acid (GLA) and arachidonic acid (AA) were administered intravenously with ceftazidime and amikacin in rabbits with sepsis caused by one multidrug-resistant isolate. Therapy was started after bacterial challenge in five groups comprising 12 animals in each group: A, normal saline; B, antimicrobials; C, 99% ethanol and antimicrobials; D, GLA and antimicrobials; and E, AA and antimicrobials. Blood was sampled for the estimation of levels of endotoxins in serum (lipopolysaccharide), leukocytes, tumor necrosis factor alpha (TNF-alpha) and antimicrobials. Animals were sacrificed 210 min after bacterial challenge for tissue cultures. All animals had considerable endotoxemia and evolved leukopenia. The number of viable cells in blood, lung, and mesenteric lymph nodes was significantly reduced in groups D and E compared to that in other groups. Levels of antimicrobials in serum were inadequate to achieve bacterial killing due to the level of resistance. n-6 PUFAs did not influence TNF-alpha. It is concluded that intravenous coadministration of n-6 PUFAs and antimicrobials enhanced antimicrobial bacterial killing in experimental sepsis caused by multidrug-resistant P. aeruginosa.

[PK/PD modeling of aminoglycoside nephrotoxicity]. / Un modèle PK/PD de la néphrotoxicité des aminoglycosides.

Aminoglycosides are bactericidial antibiotics with a serum concentration-dependent activity. They are mainly eliminated by the kidneys and the main difficulty arising in clinical use is their uptake by the renal cortex which leads to nephrotoxicity. An ototoxicity is also reported. We propose a PK/PD modelling of aminoglycoside nephrotoxicity which unifies more fourty years of physiological knowledge. This deterministic model successively describes the pharmacokinetics of aminoglycosides, their storage into renal cortex, their effect on renal cells, their consequences on the renal function through tubuloglomerular feedback and the changes in the serum concentrations of creatinine that is considered as a toxicity marker. The simulation of the model displays the leading effect of the shape and daily-time of administration schedule on the search for minimizing toxicity.

In vivo efficacy of continuous infusion versus intermittent dosing of ceftazidime alone or in combination with amikacin relative to human kinetic profiles in a Pseudomonas aeruginosa rabbit endocarditis model.

Ceftazidime and amikacin were administered in a Pseudomonas aeruginosa rabbit endocarditis model using computer-controlled intravenous (iv) infusion pumps to simulate human serum concentrations for the following regimens: continuous (constant rate) infusion of 4, 6 or 8 g of ceftazidime over 24 h or intermittent dosing of 2 g every 8 h either alone or in combination with amikacin (15 mg/kg once daily). The in vivo activities of these regimens were tested on four Pseudomonas aeruginosa strains. Animals were killed 24 h after the beginning of treatment. Efficacy was assessed by comparing the effects of the different groups on bacterial counts in vegetations for each strain tested. For a susceptible reference strain (ATCC 27853; MICs of ceftazidime and amikacin 1 and 2 mg/L, respectively), continuous infusion of 4 g alone or with amikacin was as effective as intermittent dosing with amikacin. For a clinical isolate producing an oxacillinase (MICs of ceftazidime and amikacin 8 and 32 mg/L, respectively), continuous infusion of 6 g was equivalent to intermittent dosing. For a clinical isolate producing a TEM-2 penicillinase (MIC of ceftazidime and amikacin 4 mg/L), continuous infusion of 6 g, but not intermittent dosing, had a significant in vivo effect. For a clinical isolate producing an inducible, chromosomally encoded cephalosporinase (MIC of ceftazidime and amikacin 8 and 4 mg/L, respectively), neither continuous infusion nor intermittent dosing proved effective. Determination of ceftazidime concentrations in vegetations showed that continuous infusion produced tissue concentrations at the infection site far greater than the MIC throughout the treatment. It is concluded that continuous infusion of the same total daily dose provides significant activity as compared with fractionated infusion. This study confirms that a concentration of 4-5 x MIC is a reasonable therapeutic target in most clinical settings of severe P. aeruginosa infection.