Once-daily Aminoglycoside Dosing Research Articles

Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis.

People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. This is an update of a previously published review. To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.Date of the most recent search: 31 January 2019.We also searched online trial registries. Date of latest search: 25 February 2019. All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy or toxicity or both, in people with cystic fibrosis. The two authors independently selected the studies to be included in the review and assessed the risk of bias of each study; authors also assessed the quality of the evidence using the GRADE criteria. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. We identified 15 studies for possible inclusion in the review. Five studies reporting results from a total of 354 participants (aged 5 to 50 years) were included in this review. All studies compared once-daily dosing with thrice-daily dosing. One cross-over trial had 26 participants who received the first-arm treatment but only 15 received the second arm. One study had a low risk of bias for all criteria assessed; the remaining included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias.There was little or no difference between treatment groups in: forced expiratory volume in one second, mean difference (MD) 0.33 (95% confidence interval (CI) -2.81 to 3.48, moderate-quality evidence); forced vital capacity, MD 0.29 (95% CI -6.58 to 7.16, low-quality evidence); % weight for height, MD -0.82 (95% CI -3.77 to 2.13, low-quality evidence); body mass index, MD 0.00 (95% CI -0.42 to 0.42, low-quality evidence); or in the incidence of ototoxicity, relative risk 0.56 (95% CI 0.04 to 7.96, moderate-quality evidence). Once-daily treatment in children probably improved the percentage change in creatinine, MD -8.20 (95% CI -15.32 to -1.08, moderate-quality evidence), but showed no difference in adults, MD 3.25 (95% CI -1.82 to 8.33, moderate-quality evidence). The included trials did not report antibiotic resistance patterns or quality of life. Once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.

Antibiotic Dosing in Chronic Kidney Disease and End-Stage Renal Disease: A Focus on Contemporary Challenges.

Infections are an important cause of morbidity and mortality among patients with chronic kidney disease. Therefore, appropriate antibiotic dosing is imperative to achieve positive patient outcomes while minimizing antibiotic dose-related toxicity. Accurately assessing renal function and determining the influence of renal replacement therapy on antibiotic clearance makes drug dosing in this patient population challenging. Furthermore, as technological advances in hemodialysis and peritoneal dialysis occur, research incorporating newer dialysis parameters to guide drug dosing may not be readily available. Currently, there are limited data to guide drug dosing in the setting of automated peritoneal dialysis, short daily hemodialysis, and nocturnal hemodialysis. Antibiotic-dosing recommendations should be carefully evaluated considering the accuracy of the renal function assessment, the similarity of the operating characteristics of the renal replacement therapy studied compared with those being used, and whether the dosing strategy takes advantage of the pharmacodynamic profile of the antibiotic under consideration. After implementing the antibiotic-dosing regimen, therapeutic drug monitoring should occur when possible along with careful monitoring for antibiotic efficacy and safety.

Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis.

People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. This is an update of a previously published review. To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.Date of the most recent search: 24 June 2016. All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy or toxicity or both, in people with cystic fibrosis. The two authors independently selected the studies to be included in the review and assessed the risk of bias of each study; authors also assessed the quality of the evidence using the GRADE criteria. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. Fifteen studies were identified for possible inclusion in the review. Four studies reporting results from a total of 328 participants (aged 5 to 50 years) were included in this review. All studies compared once-daily dosing with thrice-daily dosing. One study had a low risk of bias for all criteria assessed; the remaining three included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias.There was no significant difference between treatment groups in: forced expiratory volume in one second, mean difference 0.33 (95% confidence interval -2.81 to 3.48, moderate quality evidence); forced vital capacity, mean difference 0.29 (95% confidence interval -6.58 to 7.16, low quality evidence); % weight for height, mean difference -0.82 (95% confidence interval -3.77 to 2.13, low quality evidence); body mass index, mean difference 0.00 (95% confidence interval -0.42 to 0.42, low quality evidence); or in the incidence of ototoxicity, relative risk 0.56 (95% confidence interval 0.04 to 7.96, moderate quality evidence). The percentage change in creatinine significantly favoured once-daily treatment in children, mean difference -8.20 (95% confidence interval -15.32 to -1.08, moderate quality evidence), but showed no difference in adults, mean difference 3.25 (95% confidence interval -1.82 to 8.33, moderate quality evidence). The included trials did not report antibiotic resistance patterns or quality of life. Once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.

Once-daily aminoglycoside dosing: An update on current literature.

The advantages and disadvantages of once-daily versus conventional dosing of aminoglycoside antibiotics are reviewed. Although administration of multiple daily doses remains the standard method of aminoglycoside dosing, once-daily dosing may provide enhanced clinical efficacy and reduced toxicity in selected patient populations; demonstrated pharmacokinetic and pharmacodynamic advantages include enhanced postantibiotic effect and an increased likelihood of a high ratio of serum peak concentration to minimum inhibitory concentration. Published evidence identified in a MEDLINE search covering the period 1985-2014 indicates that once-daily high-dose aminoglycoside therapy generally provides clinical effectiveness equivalent or superior to that of multiple-daily dosing. The risk of nephrotoxicity appears to be comparable with once- and multiple-daily aminoglycoside dosing. Several nomograms have been developed to facilitate once-daily dosing; the Hartford nomogram (using a dose of 7 mg/kg) is the most extensively tested and generally considered the most reliable. However, although those nomograms are convenient to use and may reduce expenses, a daily dosing regimen determined by individualized pharmacokinetic monitoring is likely to be more effective for achieving specific serum concentrations and may be a preferable approach for some patients. Patients who are pregnant or have liver failure, severe renal insufficiency, serious illness, or nutritional deficiency are not appropriate candidates for once-daily dosing. Once-daily aminoglycoside dosing is an effective, well-established method to achieve therapeutic efficacy while limiting the risk of toxicity and simplifying the processes of dosing and monitoring.

Once daily dosing of aminoglycoside in children

Aminoglycosides are frequently used antibiotics in children. The multiple daily dosing (MDD) in infants and children is twice or three times daily depending on age. Recent studies in adults have shown that once daily dosing (ODD) maximizes the bactericidal activity and might minimize the toxicity of antibiotics. So, I reviewed many studies about efficacy, toxicity and cost effectiveness of ODD of aminoglycosides in children. Most studies suggest that ODD compared with MDD of aminoglycosides is theoretically more efficacious and has no higher toxicity in infants and children. But, the total number of patients included in the studies is not large. Multi-center, controlled prospective studies are required in larger numbers of infants and children to determine the efficacy and safety of the ODD regimen in children before ODD of aminoglycosides can be recommended for routine use

Once-Daily Aminoglycoside Administration

Once-daily aminoglycoside dosing is effective in treating gram-negative infections, including those associated with bones and joints.

Evaluation of Once Daily Aminoglycoside Use in the Elderly

Purpose This study evaluated the incidence of nephrotoxicity due to once daily aminoglycoside (ODA) use in elderly patients at two South Florida institutions. Methods A retrospective review of all patients who received 7 mg/kg/day of either gentamicin or tobramycin was conducted. Results Eighty-one (49%) males and 84 (51%) females with a mean age of 73 (range, 60 to 95) years were included. Nephrotoxicity was evident in 16 patients (9.7%). Of these, eight (4.8%) experienced nephrotoxicity possibly associated with aminoglycoside administration. A subgroup analysis of nonnephrotoxic patients compared with nephrotoxic patients revealed no significant differences in mean initial serum creatinine (1 mg/dL vs 0.95 mg/dL, P = 0.861) or dosing interval (31.4 vs 31.5 hours, P = 0.983). The mean duration of aminoglycoside treatment was less in the nonnephrotoxic group compared with the nephrotoxic group (5.2 vs 9.9 days, P < 0.05). Conclusion The results of this retrospective evaluation suggest that ODA dosing in the elderly is safe; however, patients should be monitored closely, especially when they require more than 5 days of aminoglycoside therapy, or are receiving concomitant nephrotoxic agents.

An Evaluation of Gentamicin, Tobramycin, and Amikacin Pharmacokinetic/Pharmacodynamic Parameters in HIV-Infected Children

The purpose of the study was to calculate gentamicin, tobramycin, and amikacin pharmacokinetic parameters in HIV-infected children and compare conventional multiple daily aminoglycoside dosing to once-daily aminoglycoside (ODA) dosing in attaining peak serum aminoglycoside concentrations (SACs) to minimum inhibitory concentration for 90% of isolates (MIC(90)) ratios ≥8 against selected pathogens. Patients (<13yrs) receiving an aminoglycoside (15 patients/drug) in the treatment of gram-negative infection were studied. Intravenous gentamicin/ tobramycin were administered at a dose of 6-7.5 mg/kg/day and amikacin at 20-30 mg/kg/d divided every 8 hrs. Peak and trough serum concentrations were obtained and pharmacokinetic parameters were calculated utilizing a one-compartment steady-state model. SACs for gentamicin/tobramycin dosed at 7.5 mg/kg and amikacin at 22.5 mg/kg once daily were simulated using the calculated pharmacokinetic parameters. Peak SAC:MIC(90) ratios were calculated for each dosing method. Mean pharmacokinetic parameters were within 1 standard deviation of reported literature values. Mean peak:MIC(90) ratio of ≥8 was attained only for Klebsiella species (MIC90 1 μg/mL) using conventional gentamicin/tobramycin dosing whereas mean amikacin peak:MIC(90) ratios ≥8 were reached for Klebsiella, Enterobacter, and Citrobacter species (MIC(90) 4 μg/mL). ODA simulations predicted gentamicin/tobramycin peak:MIC(90) ratios ≥8 in 100% of patients with an organism-MIC(90) of 1 μcg/mL and in 80% of patients with an organism-MIC(90) of 2 μg/mL. Amikacin peak:MIC(90) ratio ≥8 was predicted for 93% of patients with an organism-MIC(90) of 4 μg/mL but in only 27% if the MIC(90) was 8 μg / mL. Optimal peak SAC:MIC90 ratios using conventional aminoglycoside dosing were predicted only for organisms with low MIC(90) values. ODA dosing represents an option for improving pharmacodynamic outcomes.

Commentary: Once-daily aminoglycoside dosing: Where are we now?

bution in patients with gram-negative sepsis in the ICU. Anesthesiology 67:A126, 1987 20. Sumner WR, Michael JR, Lipsky JJ: Initial aminoglycosides levels in the critically ill. Crit Care Med 11:948-950, 1983 21. Triginer C, Izquierdo I, Fernandez R, et al: Gentamicin volume of distribution in critically ill septic patients. Intensive Care Med 16:303-306, 1990 22. Bergmans D, Bonten M: Colonization and infection with pseudomonas aeruginosa in intensive care: Endogenous or exogenous origin? Yearbook of Intensive Care and Emergency Medicine. Heidelberg, Springer Verlag, 1999, pp 131-140

Risk factors for nephrotoxicity in elderly patients receiving once-daily aminoglycosides.

There remain concerns about the safety of once-daily dosing of aminoglycosides (AGs) in the elderly. To assess the safety of once-daily AGs in elderly patients and evaluate possible risk factors for nephrotoxicity. Prospective, non-interventional surveillance study. All patients receiving AGs were monitored over 4 months. Clinicians determined the AG dose for each patient after estimating patient weight and calculating creatinine clearance (CrCl) using the Cockcroft-Gault formula. Parallel figures were calculated by the investigators using measured weight. Clinicians obtained an AG trough level 24 h after initiation of treatment, and, if non-toxic, every 5-7 days thereafter. AG toxicity was defined as an increase in serum creatinine of > or =50%. In the study period, 249 consecutive patients received an AG: 116 (47%) males, mean+/-SD age 75+/-16 years. Forty-two (17%) received amikacin and 207 (83%) gentamicin. An increase of > or =50% in serum creatinine was detected in 31/249 (12.4%); maximal creatinine was < or =177 micromol/l in 16/249 (6.4%), 186-265 micromol/l in nine (3.6%), and >265 micromol/l in six (2.4%). None developed oliguric renal failure. Renal damage correlated with a high AG trough level (>1.1 microg/ml) (p<0.001); haemoglobin level <10 g/dl (p<0.05); hospital admission >7 days prior to AG treatment (p<0.005); and AG treatment > or =11 days (p<0.05). Mean CrCl based on estimated weight was 52+/-18 ml/min; that based on actual weight was 71+/-37 ml/min. Despite this, mean AG dose was 1.3+/-0.6 higher than optimal. Oliguric and/or lasting renal toxicity is rare in elderly patients receiving once-daily aminoglycosides for <11 days, if regular trough drug levels are monitored.

Aminoglycoside nephrotoxicity: do time and frequency of administration matter?

Aminoglycosides remains the mainstay in the treatment of gram-negative infections despite their potential oto-and nephrotoxicity although alternatives with equal or better efficacy are available. Several approaches were investigated to decrease aminoglycosides nephrotoxicity. Among them, only the once-daily dosing of aminoglycosides has been brought to the clinic and physicians are now increasingly adopting this approach to reduce the toxicity of these agents. The incidence of aminoglycoside nephrotoxicity can be further reduced in view of the recent data on the circadian variations of their nephrotoxicity. In fact, it has been clearly demonstrated in both experimental animals and humans that the toxicity is maximal when the drug is injected during the rest period compared with the activity period. Thus, injecting aminoglycosides once-daily at the time of the lowest toxicity is actually the most interesting and clinically applicable approach to reduce aminoglycosides toxicity.

Once daily versus multiple daily dosing with intravenous aminoglycosides for cystic fibrosis.

Patients with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require repeated courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher concentrations less often. To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. We searched the Cystic Fibrosis specialist trials register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Date of the most recent search: February 2000. All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy and/or toxicity, in patients with cystic fibrosis. Both reviewers independently extracted data and assessed trial quality. Authors of one study were contacted to obtain missing information. Two trials reporting results from a total of 70 patients were included in this review. Both trials compared once-daily dosing with thrice-daily dosing reporting data on Forced Expiratory Volume at one second (FEV1), Forced Vital Capacity (FVC), nutritional status and side effects. There was no significant difference in efficacy or in the incidence of ototoxicity and nephrotoxicity between treatment groups. Despite a lack of difference between the two groups we feel that these results should be viewed with caution as the numbers of patients involved was small and lacks the power to detect a difference between the groups. This systematic review has highlighted the need for a well designed, adequately-powered, multicentre, randomised controlled trial assessing the efficacy of once-daily versus multiple-daily dosing of intravenous aminoglycosides for pulmonary exacerbations in cystic fibrosis.

PHARMACOKINETICS AND PHARMACODYNAMICS OF ANTIBIOTICS IN MENINGITIS

The penetration of antimicrobials into the CSF is dependent on lipid solubility, molecular size, capillary and choroid plexus efflux pumps, protein binding, and the degree of inflammation. Penicillins, certain cephalosporins, carbapenems, fluoroquinolones, vancomycin, and rifampin provide the highest ratios of CSF levels to the MBC for common infecting organisms. For beta-lactam antibiotics, it is the duration of time that CSF concentrations exceed the MBC that determines the rate of bactericidal activity. It appears that levels should exceed the MBC for more than 50% of the dosing interval. The peak/MBC and AUC/MBC ratios are important determinants of efficacy for aminoglycosides and fluoroquinolones. Once-daily dosing of aminoglycosides is as effective as multiple-daily dosing regimens in experimental meningitis, probably because of drug-induced prolonged persistent effects. Fluoroquinolones do not produce as prolonged persistent effects and are slightly less effective when administered once daily. Although steroid use can reduce the penetration and decrease the bactericidal activity of some antimicrobials, such as vancomycin, in experimental meningitis, the clinical impact of steroid use in human meningitis is still unclear.

Intraocular penetration of gentamicin after once-daily aminoglycoside dosing.

Intraocular concentrations-particularly intravitreal concentrations-after systemic administration of gentamicin are poor. Once-daily aminoglycoside dosing of intravenous gentamicin achieves peak serum levels up to five times higher than conventional dosing. Whether these increased serum levels of gentamicin improve the aqueous or vitreous concentrations in humans has not been determined. The authors sought to determine if the intraocular penetration of gentamicin would be improved using this method. Patients undergoing vitrectomy procedures were administered intravenous gentamicin in a dose of 7 mg/kg approximately 1 hour before surgery. An adjustment in dosing was made for anyone more than 20% over his or her ideal body weight. Aqueous, vitreous, and serum samples were collected before any intraocular surgical manipulation. The samples were analyzed by fluorescence polarization immunoassay (TDx system). The average single gentamicin dose was 498 mg (range, 360-700 mg). The aqueous, vitreous, and serum levels averaged 1.14 microg/mL, 0.41 microg/mL, and 22.07 microg/mL, respectively. No correlation between serum level concentrations and time of administration was found for the aqueous and vitreous levels in this study. Although the average peak serum level of gentamicin was five times higher than previously reported, the vitreous levels averaged only 1.5 times higher. The blood-retinal barrier is difficult to penetrate even when higher serum levels are achieved. Due to its poor ocular penetration, gentamicin may not be among the best drugs for prophylaxis of penetrating eye injuries, surgical prophylaxis, or treatment of endophthalmitis.

A comparison of traditional dosing and once-daily aminoglycoside dosing on non-specific antibiotic side-effects in adults

A comparison of traditional dosing and once-daily aminoglycoside dosing on non-specific antibiotic side-effects in adults

The pharmacodynamics of aminoglycosides.

Recently, a more complete understanding of the pharmacodynamics of aminoglycosides has been recognized, indicating that this class of antibiotics exhibits both concentration-dependent bactericidal activity and a postantibiotic effect. This pharmacodynamic information, along with better knowledge of the mechanisms responsible for aminoglycoside toxicity, established the foundation for once-daily aminoglycoside dosing regimens. This new approach to aminoglycoside dosing appears to be safe, efficacious, and cost-effective, resulting in its increasing popularity in clinical practice.

Once-daily aminoglycosides: practical guidelines.

There is ample evidence that once-daily dosing of aminoglycosides is preferable to the conventional regimens during the treatment of serious infections. Experimental and clinical studies also provide evidence that this regimen can be safely used in children, neutropenic patients and endocarditis. The use of once-daily tobramycin in cystic fibrosis merits further study, as the pharmacokinetics of the aminoglycosides are altered in these patients. The dose-adjustment strategy in patients with renal failure is still controversial, but reducing the daily dose whilst maintaining the q24-h interval has been demonstrated to be safe. Although the value of serum level monitoring in ensuring efficacy and avoiding toxicity has been overestimated in the past, especially in patients with renal failure, an undesirable accumulation of the aminoglycosides can occur. The best way to detect accumulation remains to be defined.

Once-Daily Aminoglycosides: A Meta-Analysis of Nonneutropenic and Neutropenic Adults

Objective: To compare the efficacy, nephrotoxicity, and ototoxicity of once-daily dosing of aminoglycosides versus conventional dosing. Design: Meta-analysis of 14 randomized trials identified through a MEDLINE search (January 1965-May 1996). Patients: Neutropenic and nonneutropenic adults. Interventions: Patients were randomly selected to receive an aminoglycoside once daily or in multiple daily doses. Measurements and Main Outcomes: The outcomes considered were clinical cure, bacteriologic cure, nephrotoxicity, auditory toxicity, and vestibular toxicity. The data were analyzed in the following subgroups: (1) all trials, (2) nonneutropenic patients, (3) neutropenic patients, and (4) patients with undefined neutrophil status. For all trials the pooled risk ratio was 1.268 (95% CI 0.828 to 1.939) for clinical cure, and was 1.390 (95% CI 1.350 to 1.392) for bacteriologic cure. Nephrotoxicity had a pooled risk ratio of 0.765 (95% CI 0.468 to 1.252), that for auditory toxicity was 1.117 (95% CI 0.151 to 5.636), and that for vestibular toxicity was 1.155 (95% CI 0.221 to 6.039). Analysis of the subgroups, including a separate analysis of neutropenic patients, demonstrated similar results. Conclusions: When all trials were considered, once-daily administration of aminoglycosides had similar efficacy and no increase in nephrotoxicity or ototoxicity compared with conventional aminoglycoside dosing.

Once-daily dosing of aminoglycosides: review and recommendations for clinical practice.

The use of higher-dose, extended interval (i.e., once-daily) aminoglycoside regimens to optimize bacterial killing is justified by a pharmacodynamic principle of aminoglycosides, namely concentration-dependent killing, and by the partial attribution of the toxicity of aminoglycosides to prolonged serum concentrations. Numerous in-vitro and animal studies have supported using once-daily aminoglycoside dosing. Clinical studies show at least equal effectiveness and no greater toxicity when compared with traditional regimens. A dose of 5-7 mg/kg of gentamicin, tobramycin, or netilmicin, with at least a 24 h dosing interval should be employed and a similar regimen can be applied to amikacin dosing. As yet, there are some patient populations that have not been adequately studied to determine whether or not once-daily aminoglycoside dosing would be a better choice than traditional dosing regimens.

Adaptive resistance of Pseudomonas aeruginosa induced by aminoglycosides and killing kinetics in a rabbit endocarditis model.

Adaptive resistance following the first exposure to aminoglycosides is a recently described in vitro phenomenon in Pseudomonas aeruginosa and other aerobic gram-negative bacilli. We investigated the in vivo relevance of adaptive resistance in P. aeruginosa following a single dose of amikacin in the experimental rabbit endocarditis model. Rabbits with P. aeruginosa endocarditis received either no therapy (control) or a single intravenous (i.v.) dose of amikacin (80 mg/kg of body weight) at 24 h postinfection, after which they were sacrificed at 5, 8, 12, 16, or 24 h postdose. Excised aortic vegetations were subsequently exposed ex vivo to amikacin at 2.5, 5, 10 or 20 times the MIC for 90 min. In vivo adaptive resistance was identified when amikacin-induced pseudomonal killing within excised aortic vegetations was less in animals receiving single-dose amikacin in vivo than in vegetations from control animals not receiving amikacin in vivo. Maximal adaptive resistance occurred between 8 and 16 h after the in vivo amikacin dose, with complete refractoriness to ex vivo killing by amikacin seen at 12 h postdose. By 24 h postdose, bacteria within excised vegetations had partially recovered their initial amikacin susceptibility. In a parallel treatment study, we demonstrated that amikacin given once daily (but not twice daily) at a total dose of 80 mg/kg i.v. for 1-day treatment significantly reduced pseudomonal densities within aortic vegetations versus those in untreated controls. When therapy was continued for 3 days with the same total daily dose (80 mg/kg/day), amikacin given once or twice daily significantly reduced intravegetation pseudomonal densities versus those in controls. However, amikacin given once daily was still more effective than the twice-daily regimen. These data confirm the induction of aminoglycoside adaptive resistance in vivo and further support the advantages of once-daily aminoglycoside dosing regimens in the treatment of serious pseudomonal infections.