***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Two doses of gentamicin ( 2 and 7 mg/kg of body weight ) were administered to 11 healthy volunteers in a r and omized , crossover single-dose study to compare their pharmacokinetics . Doses were infused over 1 h with a syringe infusion pump , and 14 concentrations in sera were obtained over an 8-h period . Concentration in serum versus time data were fitted to a two-compartment pharmacokinetic model . In addition , to mimic the clinical setting , subjects ' data were fitted by the Sawchuk-Zaske method . Distributional and postdistributional peak concentrations , along with the last obtained concentration in serum , were utilized to compare the following pharmacokinetic variables : volume of distribution at steady state ( Vss ) , half-life , clearance ( CL ) , and maximum concentration in serum ( Cmax ) . With two-compartment pharmacokinetic fitting , significant differences in distribution half-life ( average , 21.8 and 41.6 min [ P < or = 0.05 ] ) and gentamicin CL ( 76.6 + /- 6.6 and 67.2 + /- 4.2 ml/min/1.73 m2 [ P < or = 0.001 ] ) were found between traditional-dose and high-dose groups , respectively . When the data for concentrations in sera were fitted to a one-compartment pharmacokinetic model by using either the distributional or the postdistributional Cmax , statistically significant differences ( P < or = 0.001 ) were found between Vss , half-life , CL , and Cmax values for both dosage groups . The results show that the pharmacokinetics of gentamicin at a large dose differ significantly from those at the traditional dose . This information has direct implication s for once-daily aminoglycoside ( ODA ) literature when the Cmax values reported are distributional and therefore show falsely high Cmax/MIC ratio estimates . In addition , ODA nomogram dosing tools developed with distributional Cmax values are probably inaccurate ABSTRACT Once-daily ( o.d . ) administration of 20 mg of amikacin per kg of body weight to neutropenic patients has been vali date d by clinical studies , but amikacin pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily ( b.i.d . ) regimen in this population . In order to determine in neutropenic patients ( i ) the influence of the dosing regimen on the kinetics of amikacin , ( ii ) the linearity of kinetics of amikacin in the range of 7.5 to 20 mg/kg , and ( iii ) the influence of patient characteristics on the disposition of amikacin and ( iv ) to provide a rationale for dosing recommendations , we evaluated the population pharmacokinetics of amikacin administered to 57 febrile neutropenic adults ( neutrophil count , < 500/mm3 ) being treated for a hematological disorder and receiving amikacin at 7.5 mg/kg b.i.d . ( n = 29 ) or 20 mg/kg o.d . ( n = 28 ) and administered intravenously over 0.5 h. A total of 278 blood sample s were obtained ( 1 to 14 sample s per patient ) during one or several administration intervals ( 1 to 47 ) . Serum amikacin levels were measured by the enzyme-multiplied immunoassay technique . A mixed-effect modeling approach was used to fit a bicompartmental model to the data ( NONMEM software ) . The influences of the dosing regimen and the demographic and biological indices on the pharmacokinetic parameters of amikacin were evaluated by the maximum-likelihood ratio test on the population model . The dosing regimen had no influence on amikacin pharmacokinetic parameters , i.e. , the kinetics of amikacin were linear over the range of 7.5 to 20 mg/kg . Amikacin elimination clearance ( CL ) was only correlated with creatinine clearance or its covariates , namely , sex , age , body weight , and serum creatinine level . The interindividual variability of CL was 21 % , while those of the central volume of distribution , the distribution clearance , and the tissue volume of distribution were 15 , 30 , and 25 % , respectively . On the basis of the expected distribution of amikacin concentrations in this population , dosing recommendations as a function of creatinine clearance ( CLCR ) are proposed : for patients with normal renal function ( CLCR of 80 to 130 ml/min ) , 20 mg/kg o.d . is recommended , whereas for patients with severe renal impairment ( CLCR , 10 to 20 ml/min ) , a dosage of 17 mg/kg every 48 h is recommended Isepamicin is a new aminoglycoside with in-vitro activity superior to amikacin . It is a poor substrate for the 6'-aminoacetyltransferase-I enzyme which inactivates amikacin and therefore organisms possessing this enzyme are not resistant to isepamicin . The aim of this study was to compare the efficacy and safety of co-administration of isepamicin once daily plus ceftriaxone to amikacin twice daily plus ceftriaxone to amikacin twice daily plus ceftriaxone in febrile neutropenic cancer patients . Febrile episodes in 235 patients ( 156 in isepamicin group and 79 in amikacin group ) were treated in this study . They occurred in 218 different patients . Fifteen patients were enrolled twice and one three times .  Response rates to the two treatment regimens for microbiologically documented episodes , clinical ly documented episodes and further unexplained fever were similar . Tolerance of the treatment regimens , as measured by serum creatinine levels , hypoaccousia and cutaneous allergy was also similar in both treatment groups . In conclusion , isepamicin given once daily when combined with ceftriaxone in the treatment of  febrile episodes in neutropenic cancer patients was as effective and no more toxic than amikacin In a prospect i ve , r and omized trial , netilmicin given once daily ( OD ) was compared in terms of efficacy and safety with the conventional 8-hourly dosing regimen ( TD ) , both in combination with a broad spectrum beta-lactam , as initial empirical therapy for febrile neutropenic patients ; the total daily dosage of netilmicin in each group was 6 mg/kg body weight . Twenty-nine of the 116 ( 25 % ) evaluable patients had microbiologically documented septicaemia , most of which were caused by Gram-positive bacteria , 41 ( 35 % ) had microbiologically documented infection without bacteraemia and 46 ( 40 % ) had possible infection .  Highest peak serum concentrations of netilmicin in the OD group were significantly higher and trough serum concentrations significantly lower than in the TD group . A multivariate analysis revealed that neither the dosage regimen nor the peak serum concentration of netilmicin were determinants of a favourable outcome . The response rates of both groups to the initial treatment regimens were comparable and increased similarly following modification of the initial therapy . Response rates were particularly poor in patients with lower respiratory tract infection and in those who remained neutropenic throughout the course of treatment . The incidence of nephrotoxicity was low and did not differ significantly between groups . Once-daily dosing of netilmicin appears to be as effective and as safe as thrice-daily dosing , but is unlikely to further improve the response of febrile neutropenic patients to empirical therapy Recently , much interest has focused on the use of once-daily aminoglycosides ( ODA ) in the medical literature . In late 1992 , we implemented a hospital-wide ODA program  for adult patients at our 850-bed community-teaching hospital . In the first phase of implementation , therapeutic drug monitoring ( TDM ) was accomplished with the use of a r and om serum concentration and a nomogram that had been developed at our institution . In the second phase , serum drug concentrations were eliminated on patients with normal renal function . The fully implemented program result ed in a 40 % decrease in the request for gentamicin and tobramycin serum concentrations as compared with historic ordering patterns for conventional aminoglycoside dosing regimens . In addition , the incidence of nephrotoxicity was also reduced from 3 to 5 % with conventional aminoglycoside dosing , to 1.2 and 1.3 % for phases 1 and 2 , respectively . Furthermore , the elimination of TDM requests totaling 300 for gentamicin and 50 for tobramycin per month is expected to result in an annual institutional savings of > $ 100,000 The pathogenesis of aminoglycoside nephrotoxicity is directly related to the accumulation of drug within the renal cortex . To identify measures that might prevent aminoglycoside nephrotoxicity , we investigated the influence of various dosage regimens on the renal cortical accumulation of amikacin and tobramycin in man . Patients undergoing nephrectomy for a renal tumour with normal renal function and no proteinuria received ( i ) a single dose of either amikacin ( 15 mg/kg ) or tobramycin ( 4.5 mg/kg ) given iv over 30 min , or ( ii ) a 24-h continuous infusion of either drug or ( iii ) amikacin as two injections of 7.5 mg/kg or tobramycin as three injections of 1.5 mg/kg over the 24 h preceding nephrectomy . Serum aminoglycoside pharmacokinetics were examined and renal cortical tissue was sample d for drug determination at operation . A single injection yielded cortical concentrations of 115.4 + /- 21.8 and 68.9 + /- 30.3 mg/kg for amikacin and tobramycin , respectively . Tissue levels after continuous infusion were 171.7 + /- 42.9 and 100.0 + /- 30.0 mg/kg for amikacin and tobramycin , respectively . Two injections of 7.5 mg/kg amikacin result ed in renal cortical concentrations of 196.9 + /- 54.9 and three injections of 1.5 mg/kg tobramycin result ed in renal cortical concentration of 76.5 + /- 18 mg/kg . The AUC for the three dosage regimens was not significantly different for the two aminoglycosides indicating linear serum pharmacokinetics for these drugs . In the case of amikacin , a single injection result ed in significantly lower drug levels than did a continuous infusion or administration of the same dose over three injections . ( ABSTRACT TRUNCATED AT 250 WORDS Hematologic malignancies and cancer patients who become neutropenic as a result of disease or myelosuppressive cytotoxic therapy are at a high risk of developing life-threatening infections , and hence empirical antibiotic therapy is administered promptly . We investigated once daily regimen of amikacin , for dose-dependent bactericidal activity and post-antibiotic effects , plus ceftriaxone , with a long-half life to maximise time-dependent bactericidal activity . Microbiologically proven septicemia were 11 out of 49 febrile episodes ( 22.5 % ) and 10 ( 91 % ) of these were due to gram-negative bacilli , mostly Enterobacteriaceae . The overall success of the regimen was 63.3 per cent of patients , with no significant toxicity . In conclusion , our findings suggest that once-daily administration of amikacin plus ceftriaxone in the initial treatment of febrile episodes in neutropenic patients produces satisfactory results and more cost-effective compared with other antibiotic regimens requiring 3 - 4 doses a day To determine the safety of single daily dose ( SDD ) gentamicin in recipients of stem cell transplantation ( SCT ) , we evaluated all adult patients at MD And erson Cancer Center who received SDD gentamicin for treatment of febrile neutropenia . Thirty-three patients received gentamicin 5 mg/kg i.v . every 24 h. Mean duration of therapy was 7 days ( range 3–32 days ) . All patients received vancomycin and 17 received cisplatinum .  All patients had normal renal function prior to therapy .  Serum gentamicin levels were monitored only when renal function deteriorated . The incidence of nephrotoxicity and clinical ly significant ototoxicity was 3 % and 12 % , respectively . All four patients who developed ototoxicity had normal renal function before and during therapy . The mean duration of gentamicin therapy was significantly longer in patients who developed ototoxicity , 20 days vs 9 days ( P = 0.001 ) . Patients treated with SDD gentamicin for > 10 days were more likely to develop ototoxicity ( P = 0.045 ) . Single daily dosing of gentamicin was associated with clinical ly significant ototoxicity in 12 % of our patients . A larger r and omized EORTC trial evaluating SDD vsMDD amikacin failed to detect a difference in ototoxicity . However , the median duration of therapy was only 8 days . The increased incidence of ototoxicity in our study may be due to prolonged therapy , type of aminoglycoside used , concomitant ototoxic agents , small sample size , or a combination of the above Prolonged distribution time has been noted for high-dose ( 7 mg/kg ) gentamicin . Higher doses are used for extended-interval aminogly 
    Output:
    
Review of the 5 studies with level I evidence ( all open-label r and omized controlled trials ) , which compared extended-interval dosing with multiple-daily dosing strategies , revealed no evidence to suggest superiority of one regimen over the other in terms of clinical outcomes .
In the study with level II-2 evidence ( a prospect i ve comparative trial ) , the response rate was better in the extended-interval group than in the st and ard-therapy group .
Two of the studies with level III evidence ( both prospect i ve noncomparative trials ) also had acceptable response rates to extended-interval aminoglycoside therapy , with minimal associated nephrotoxicity .
In this review , no major differences in rates of nephrotoxicity or ototoxicity were seen between the 2 dosing regimens .
The use of extended-interval dosing for aminoglycosides , in combination with other recommended antibiotic therapy , is an effective and safe management strategy for immunocompromised patients with febrile neutropenia .
In this population , the clinical efficacy and safety of extended-interval dosing does not appear to differ from those of st and ard dosing .