Anti-Pseudomonas activity in bronchial secretions of patients receiving amikacin or tobramycin as a continuous infusion.

The penetration of amikacin and tobramycin into bronchial secretions and the resulting anti-Pseudomonas activity were assessed in two groups of tracheostomized or intubated patients with tracheobronchial infection and purulent bronchial secretions. The aminoglycosides were administered as continuous, high-dose intravenous infusions. The mean drug concentrations in serum and bronchial secretions were 12.8 and 2.0 microgram/ml for amikacin and 3.6 and 0.7 microgram/ml for tobramycin. The bronchial secretion/serum ratios varied over a wide range: from 9.6 to 22.8% (average, 14.9%) for amikacin and from 3 to 39.3% (average, 17.5%) for tobramycin. Sustained anti-Pseudomonas activities in bronchial secretions were achieved only in patients with very high aminoglycoside levels in serum. In most patients, however, no anti-Pseudomonas activity could be detected within bronchial secretions despite therapeutic levels of amikacin and tobramycin and adequate bactericidal activities in serum.     

Evaluation of commercial assays for vancomycin and aminoglycosides in serum: a comparison of accuracy and precision based on external quality assessment

OBJECTIVE: To compare the accuracy and precision of commercial assay techniques in the measurement of gentamicin, tobramycin, amikacin, netilmicin and vancomycin in serum. METHODS: Data from the measurement of 40 external quality assessment samples from 358 laboratories providing a therapeutic drug monitoring service were analysed. RESULTS: Significant differences between techniques in accuracy and precision were observed for all drugs. Coefficients of variation ranged from 4.1% to 9.8% for the aminoglycosides and from 6.7% to 11.7% for vancomycin. The percentage difference in measurements from the weighed-in drug concentration ranged from -10.1% to +4.0% for the aminoglycosides and from -3.5% to +5.7% for vancomycin. The Dade Behring Emit immunoassay was notable in producing significantly more outliers (>4 S.D. from the weighed-in concentration) than other techniques in the measurement of gentamicin, amikacin and vancomycin. CONCLUSIONS: All assays performed to a satisfactory standard for measurement in non-renal patients, but none met the more stringent standards desirable for monitoring patients with renal impairment.     

Extended-interval dosing of tobramycin in neonates: implications for therapeutic drug monitoring

OBJECTIVE: Our objective was to individualize tobramycin dosing regimens in neonates of various gestational ages with use of early therapeutic drug monitoring. METHODS: This study was performed in neonatal patients with suspected septicemia in the first week of life. All patients received tobramycin, 4 mg/kg per dose, as a 30-minute intravenous infusion, with a gestational age-related initial interval of 48 hours (<32 weeks), 36 hours (32-36 weeks), and 24 hours (> or =37 weeks). The target serum peak and trough serum concentrations were 5 to 10 mg/L and 0.5 mg/L, respectively. Serum trough samples and 1- and 6-hour samples were taken after the first dose. Tobramycin concentrations were used to obtain gestational age-dependent population models with nonparametric expectation maximization software. To investigate the effect of timing of sampling in a second group of patients, serum trough samples and 3- and 8-hour samples were taken after the first dose of tobramycin was administered. Serum trough concentrations were predicted by use of linear pharmacokinetics in both groups and by use of the population models with bayesian feedback of 1 or 2 serum concentrations in the second group. These predicted concentrations were compared with actual serum trough concentrations. The predictive performance of the 1- to 6-hour and 3- to 8-hour models and the population models were compared with a gestational age-related model without therapeutic drug monitoring. RESULTS: A total of 247 patients were analyzed: 206 with 1- to 6-hour serum samples and 41 with 3- to 8-hour serum samples. Peak serum concentrations were above 5 mg/L in 90.8% of cases, and trough serum concentrations were above 1 mg/L in 25.5% of cases. The 3- to 8-hour linear model had a bias of -0.31 mg/L and a precision of 0.48 mg/L, and it performed significantly better than the 1- to 6-hour model. The best nonparametric expectation maximization model had a bias of -0.11 mg/L and a precision of 0.45 mg/L. None of the models yielded a significant improvement of predictive performance over the model without therapeutic drug monitoring. CONCLUSIONS: Routine early therapeutic drug monitoring does not improve the model-based prediction of initial tobramycin dosing intervals in neonates in the first week of life.     

Dosage adjustment and clinical outcomes of long-term use of high-dose tobramycin in adult cystic fibrosis patients.

A two-phase study was undertaken designed to investigate the impact of computer-aided drug monitoring on tobramycin concentrations and clinical outcomes in adult patients with cystic fibrosis. In phase one, a baseline (historical control) study of drug use patterns was performed. During the second phase, patients admitted for intravenous treatment with tobramycin for acute exacerbations of pseudomonal pulmonary infections were randomly allocated to one of two schedules. Group A patients had tobramycin dosage regimens decided by clinicians based on pre-existing protocols using serum tobramycin assay data determined three times weekly. Group B patients had dosage regimens determined by a computerized pharmacokinetic predictive program using both population-based pharmacokinetic parameter estimation and fitting of serum concentration-time data using Bayesian regression. The agreed therapeutic target was a peak serum tobramycin concentration of 8-10 mg/L and a trough concentration of 1-2 mg/L. There was a major difference between the two groups comparing the number of paired trough and peak concentrations within the target concentration ranges (group A-14%; group B-34.7%, chi 2 test, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cefotaxime aminoglycoside interactions

Minimum inhibitory concentrations and minimum bactericidal concentrations were determined for cefotaxime, gentamicin, tobramycin and amikacin and for the combination of cefotaxime and each of the aminoglycosides in vitro against 200 strains of Enterobacteriaceae. 91% were susceptible to cefotaxime, 93.5% were susceptible to gentamicin, 89.5% were susceptible to amikacin and 68% were susceptible to tobramycin. There were 95 strains which could be evaluated for synergistic killing by the antimicrobial combinations. Synergism was shown against 78% of strains by cefotaxime and amikacin, against 71% by cefotaxime and tobramycin and against 64% by cefotaxime and gentamicin. In 19 of 22 instances where a bacterial strain was resistant to both cefotaxime and the aminoglycoside, synergistic killing with clinically achievable levels of both antimicrobial agents was demonstrated. There was no significant decrease in concentration of any of the three aminoglycosides after incubation with cefotaxime at 37 degrees C for 0, 4 or 24 h.     

Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients receiving aminoglycosides.

Risk factors predisposing to auditory toxicity of aminoglycosides were analyzed from records of 187 patients enrolled in three prospective randomized trials comparing the toxicity of netilmicin, tobramycin, and amikacin. Patients were eligible if they received three or more days of therapy and at least two serial audiograms were available. The overall auditory toxicity rate was 9.6% (18 of 187). Auditory toxicity was detected in 4.4, 10.8, and 23.5% of patients given netilmicin, tobramycin, and amikacin, respectively (P = 0.05). In the univariate analysis, patients who developed auditory toxicity were significantly older (P = 0.01) and had a significantly higher (P = 0.04) percentage of trough levels of netilmicin or tobramycin above 2 mg/liter or amikacin above 5 mg/liter. In the final logistic regression model, only age was retained as independently influencing the development of auditory toxicity (P less than 0.00001). Conversely, factors that did not add significantly to the prediction of auditory toxicity were aminoglycoside serum levels, total aminoglycoside dose, duration of therapy, sex, peak temperature, presence of bacteremia, shock, liver cirrhosis, dehydration, previous otic pathology or renal failure, and development of renal toxicity. At least in certain populations, age is the most important predisposing factor for the development of auditory toxicity in patients receiving aminoglycosides.     

Comparative in vitro antimicrobial susceptibilities of nosocomial isolates of Acinetobacter baumannii and synergistic activities of nine antimicrobial combinations.

The in vitro susceptibilities of 69 nosocomial Acinetobacter isolates were determined by the broth microdilution method. Fourteen (20%) isolates were resistant to at least two aminoglycosides and two extended-spectrum penicillins. Nine antimicrobial combinations were then tested for synergy against these 14 isolates by checkerboard titration: imipenem with ciprofloxacin, amikacin, and tobramycin and ampicillin-sulbactam, piperacillin-tazobactam, and ticarcillin-clavulanate with amikacin and tobramycin. Synergy was detected with one or more antimicrobial combinations against 9 of 14 (64%) isolates, partial synergy was detected with one or more combinations against all 14 isolates, and an additive effect alone was observed with two different combinations against two isolates. No antagonism was detected with any combination. Imipenem plus either amikacin or tobramycin resulted in a synergistic or partial synergistic response against all 14 isolates. Specific combinations showing synergy against A. baumannii isolates were imipenem with tobramycin (four isolates), imipenem with amikacin (three isolates), ampicillin-sulbactam with tobramycin (six isolates), ampicillin-sulbactam with amikacin (three isolates), and ticarcillin-clavulanate with tobramycin (one isolate). Genotyping by randomly amplified polymorphic DNA analysis showed that 9 of the 14 isolates were of one strain, 4 isolates were of a second strain, and the remaining isolate was of a different strain. Eight of 14 (57%) patients infected with resistant A. baumannii isolates died. Only 3 of 14 patients had received a therapeutic regimen which was tested for synergy. Clinical studies are needed to determine the significance of these findings.     

Pseudomonas aeruginosa bacteremia: susceptibility of 100 blood culture isolates to seven antimicrobial agents and its clinical significance.

The susceptibility of 100 blood culture isolates of Pseudomonas aeruginosa observed during 4 1/2 years was tested for tobramycin, netilimicin, gentamicin, amikacin, pirbenicillin, ticarcillin and carbenicillin, singly and in combination. For aminoglycosides, the agar MICs were twofold to threefold greater than tube dilution MICs but for the penicillins they were similar. For aminoglycosides and ticarcillin, the MBCs were twofold greater than the tube dilution MICs. The MBCs were not achieved at concentrations as high as 512 micrograms/ml for 40% of the isolates for pirbenicillin and for 10% for carbenicillin. Tobramycin and pirbenicillin had the lowest MICs for the aminoglycosides and penicillins, respectively. Synergism was tested and observed between tobramycin + ticarcillin and amikacin + ticarcillin. No overall increase in resistance to gentamicin or carbenicillin was seen from 1974 to 1977. However, patients given repeated courses of gentamicin had more resistant strains. Following the administration of 1.5 mg/kg/dose of gentamicin, peak serum concentrations failed to achieve the MIC for the microorganism in 22% of the patients. The MIC was achieved in all patients receiving the same dose of tobramycin. The overall fatality rate was 67% with one third of the patients dying within 36 hr. There was no relationship of patient fatality rate and MIC for the microorganism. Although in the rapidly fatal group of all patients receiving inappropriate therapy died, the fatality rates of appropriately or inappropriately treated patients in the ultimately fatal and nonfatal groups were similar. Underlying host disease was the major determining factor in patient survival.     

Animal model distinguishing in vitro from in vivo carbenicillin-aminoglycoside interactions.

Aminoglycosides and carbenicillin are frequently co-administered to patients with serious gram-negative infections. Aminoglycosides are inactivated by carbenicillin in vitro, and a loss of antibacterial activity of both antibiotics results. Although these interactions are presumed to occur in vivo, previous studies have not used assay methodology that can distinguish inactivation occurring prior to and during microbiological assay from inactivation in vivo. To address this problem, we gave seven bilaterally nephrectomized mongrel dogs doses designed to achieve simultaneous therapeutic serum concentrations of aminoglycosides and carbenicillin. Serum samples were tested by radioimmunoassay on three occasions: immediately, to determine in vivo interactions, and at 24 h and 1 week to assess the time course of in vitro inactivation. In comparison with immediate radioimmunoassay, gentamicin and tobramycin concentrations decreased by 39 and 53%, respectively, when assayed at 24 h (P < 0.05) and by 75 and 82% when assayed at 7 days (P < 0.001). In contrast, amikacin concentrations were reduced by only 9 and 30% at 24 h and 7 days. Tobramycin concentrations were also determined by immediate microbiological assay and were found to be similar to those in samples stored for 24 h before radioimmunoassay. Immediate radioimmunoassay demonstrated that carbenicillin reduced in vivo serum half-lives of gentamicin and tobramycin by 40% (P < 0.05). The half-life of amikacin in vivo was not significantly altered. In the presence of carbenicillin, amikacin was the most stable aminoglycoside both in vivo and in vitro, and it is the aminoglycoside of choice in patients with renal failure who require this combination.     

Therapeutic drug monitoring of gentamicin: a 6‐year follow‐up audit

Background and objective : In 1984 a therapeutic drug monitoring (TDM) service was established in Hospital Universiti Sains Malaysia (HUSM) and gentamicin concentrations were measured and used to design optimal regimens for the antibiotic. In this study we report on a 6‐year follow‐up audit since our first assessment of the service. Method : Records of 733 requests for gentamicin monitoring were reviewed. Results : Of the 592 patients involved, 39% were neonates and 42% were adults. Peak gentamicin concentrations were within the therapeutic range in 65% of the patients at first monitoring and 79% of the corresponding trough concentrations were within the non‐toxic range. After dosage adjustment, 81% of the peak concentrations were within the therapeutic range and trough concentrations rose to levels regarded as toxic in 7% of patients. In patients with therapeutic peak concentrations at the first monitoring point, the average duration of gentamicin therapy was statistically shorter than in those patients who failed to achieve a therapeutic peak concentration. The distribution of gentamicin peak and trough concentrations in terms of therapeutic ranges were also better than those found in 1990. Conclusion : TDM for gentamicin is well accepted in HUSM and its application has contributed to improved gentamicin administration. Furthermore, our physicians are now able to choose more appropriate dosage regimens for their patients because the majority of gentamicin concentrations attained even at the first monitoring were within the therapeutic range.     

Assay of Gentamicin and Tobramycin in Sera of Patients by Gas-Liquid Chromatography

Therapeutic levels of gentamicin and tobramycin in the sera of patients were measured by gas-liquid chromatography. Concentration-response curves for both drugs were linear over an expected therapeutic range of 1.3 to 12.5 mug/ml (coefficient of determination was >0.97). Coefficients of variation for chromatographic response to gentamicin varied from 6.3 to 9.6%, and to tobramycin from 3.8 to 13.5%. Paired gas-liquid chromatography and microbiological assays for patient serum aminoglycoside levels were performed on 106 gentamicin and 40 tobramycin sera. At levels <2.0 mug/ml, the average difference of estimates between the two assay techniques for gentamicin and tobramycin were, respectively, 38 and 29%. At drug concentrations >2.0 mug/ml, the mean difference between paired estimates was near 20% for both aminoglycosides. The speed, precision, and accuracy of the gas-liquid chromatography assay indicate that it can be a useful alternative to the microbiological procedure for the determination of gentamicin and tobramycin levels in human serum.     

The prevalence of high-level aminoglycoside resistance among enterococci isolated from blood cultures during 1980-1988

Two hundred and eighty-one strains of enterococci isolated from blood cultures of 281 consecutive patients during 1980-1988 and 108 strains of enterococci isolated from miscellaneous clinical materials during 1988 were studied for high-level resistance (MIC greater than 2000 mg/l) to amikacin, kanamycin, streptomycin, gentamicin, tobramycin and netilmicin. Before 1985 there was no enterococcal strain with high-level resistance to amikacin, gentamicin, tobramycin or netilmicin, but 14% were resistant to kanamycin and 21% to streptomycin. For strains isolated from blood cultures during 1985-1988, the prevalence of high-level resistance was as follows: amikacin, less than 1%; kanamycin, 35%; streptomycin, 26%; gentamicin, 9%; tobramycin, 9%, netilmicin, 4%. Prevalence of high-level aminoglycoside resistance of enterococci isolated from miscellaneous sources during 1988 was higher (amikacin, 5%; kanamycin, 37%; streptomycin, 31%; gentamicin, 24%, tobramycin, 27%; netilmicin, 10%). Among strains isolated from blood cultures between 1980-1984, 24% (30 of 126 strains) and among 1985-1988 strains, 40% (62 of 155 strains) were resistant to at least one of the aminoglycosides tested. Similarly, among the miscellaneous strains, 40% (43 of 108 strains) had high-level resistance to at least one of the aminoglycosides tested.     

Aminoglycoside and vancomycin serum concentration monitoring and mortality due to neonatal sepsis in Saudi Arabia

OBJECTIVE: To assess the effectiveness of monitoring of serum concentration of aminoglycosides in neonates. METHOD: A retrospective evaluation of serum concentration monitoring of aminoglycosides (gentamicin and amikacin) and vancomycin in neonates treated for sepsis in a maternity and children hospital in Jeddah, Saudi Arabia, over the period 1998-2000. RESULTS: The total number of requests for monitoring increased sixfold in 1999 and 12-fold in 2000 relative to 1998. For aminoglycosides, the incidence of both subtherapeutic peak and toxic trough serum levels decreased significantly (P < 0.05) in 1999 and 2000 compared with 1998. Furthermore, the rate of neonatal mortality caused by sepsis showed reduction in both 1999 (34%) and 2000 (35%) in comparison with 1998 (45%). Vancomycin trough (effective) concentration monitoring revealed no change in the incidence (30%) of levels at subtherapeutic values (<5.0 microg/mL) between the compared years. Furthermore, the rate of toxic levels (>10 microg/mL) increased in both 1999 (31%) and 2000 (39%) relative to 1998 (25%). CONCLUSION: Therapeutic drug monitoring of vancomycin needs re-evaluation in the hospital to explain why existing methods are ineffective.     

Comparison of the nephrotoxicity and auditory toxicity of tobramycin and amikacin

A total of 157 patients were treated with tobramycin or amikacin in a controlled prospective randomized trial. Dosages were adjusted to renal function according to a nomogram. Trough and peak aminoglycoside levels were available at the end of the trial. Of the above total, 113 recipients of nine or more doses of tobramycin or six or more doses of amikacin, without other apparent cause of renal failure, were evaluated for nephrotoxicity. Thirty-six patients were evaluated for auditory toxicity. The patients in groups evaluated for either nephrotoxicity or auditory toxicity were similar with respect to intensity and etiology of bacterial disease, concurrent exposure to other antimicrobial drugs, age and sex distribution, initial serum creatinine level, and total dose and duration of antimicrobial therapy. Nephrotoxicity of similar severity developed in 4 of 59 (6.8%) recipients of tobramycin and in 7 of 54 (13.1%) recipients of amikacin (P greater than 0.05). Mild auditory toxicity developed in 3 of 19 (15.7%) recipients of tobramycin and in 2 of 17 (11.7%) recipients of amikacin (P greater than 0.05). When patients with abnormally high mean trough or peak aminoglycoside levels were excluded from comparison, nephrotoxicity was 6.12 and 5.12% (P greater than 0.05) and auditory toxicity was 17.6 and 7.69% (P greater than 0.05) in the groups given tobramycin and amikacin, respectively. We conclude that the nephrotoxicity and auditory toxicity of amikacin and tobramycin are not significantly different and that such toxicities are indeed infrequent events when the dosages of these drugs are adjusted to hold blood levels within the safe boundaries suggested by the studies of others.     

In vitro and in vivo activities of antimicrobials against Nocardia brasiliensis

In Mexico mycetomas are mostly produced by Nocardia brasiliensis, which can be isolated from about 86% of cases. In the present work, we determined the sensitivities of 30 N. brasiliensis strains isolated from patients with mycetoma to several groups of antimicrobials. As a first screening step we carried out disk diffusion assays with 44 antimicrobials, including aminoglycosides, cephalosporins, penicillins, quinolones, macrolides, and some others. In these assays we observed that some antimicrobials have an effect on more than 66% of the strains: linezolid, amikacin, gentamicin, isepamicin, netilmicin, tobramycin, minocycline, amoxicillin-clavulanic acid, piperacillin-tazobactam, nitroxolin, and spiramycin. Drug activity was confirmed quantitatively by the broth microdilution method. Amoxicillin-clavulanic acid, linezolid, and amikacin, which have been used to treat patients, were tested in an experimental model of mycetoma in BALB/c mice in order to validate the in vitro results. Linezolid showed the highest activity in vivo, followed by the combination amoxicillin-clavulanic acid and amikacin.     

Tobramycin dosing in mechanically ventilated patients. Inaccuracy of a 'rule of thumb'

The ability of a simple rule of thumb, based on creatinine clearance, to predict tobramycin serum concentrations was evaluated in mechanically ventilated patients. They were given tobramycin intravenously over 30 min at 8 h intervals. Creatinine clearance was estimated from the formula developed by Cockcroft & Gault (1976, Nephron 16, 31-41) or was calculated after urine collection for 24 h. The loading dose was 1.5 mg/kg and then dose adjustments were performed on a daily basis. Patients were studied on day 1 and day 3. Mean values of peak and trough levels were within the therapeutic range, but individual values were outside the therapeutic range in 30% to 70% of patients on both day 1 and day 3, most of the patients having subtherapeutic serum concentrations. This was mainly related to the high volume of distribution of tobramycin calculated in these patients. These results further emphasize the need to monitor serum concentrations and to use an individual pharmacokinetic method to make dose adjustment.     

Efficacy of apalcillin alone and in combination with four aminoglycoside antibiotics against Pseudomonas aeruginosa

The in vitro activity of apalcillin against 258 Pseudomonas aeruginosa strains was compared with that of 3 penicillins and 5 aminoglycosides using agar dilution tests. Apalcillin showed the highest activity of all the penicillins investigated, and of the aminoglycosides tested tobramycin and amikacin were most active. On testing the combined efficacy of apalcillin with aminoglycosides by the checkerboard technique, combinations with tobramycin or amikacin were less synergistic than combinations with gentamicin or netilmicin. Antagonistic or even only additive effects were found with none of the P. aeruginosa strains.     

Comparative susceptibilities of Pseudomonas aeruginosa to 1-oxacephalosporin (LY 127935) and eight other antipseudomonal antimicrobial agents (old and new)

In vitro susceptibilities of 53 clinical isolates of Pseudomonas aeruginosa to nine antipseudomonal antibiotics were determined. From 96 to 100% of the isolates were susceptible to piperacillin, ticarcillin, and 1-oxacephalosporin (LY 127935). Of the aminoglycosides, 89, 82, 79, and 29% were susceptible to amikacin, tobramycin, gentamicin, and netilmicin, respectively. A total of 96% and 78% of the isolates were susceptible to 1-oxacephalosporin (LY127935) and cefotaxime, respectively, at concentrations of 62.5 micrograms/l. Supplementation of testing media by calcium and magnesium not only markedly increased the minimal inhibitory concentrations of the aminoglycosides, but also raised those of cefotaxime and the penicillins; no significant effect was noted with 1-oxace-phalosporin. Synergy was not demonstrated consistently in vitro with 1-oxace-phalosporin combined with either carbenicillin, ticarcillin, gentamicin, or tobramycin.