The relative influence of peak concentration (Cmax) versus the area under the antibiotic concentration-time curve (AUC) on the bactericidal effect of gentamicin against Escherichia coil NCTC 10418 was studied. Bacteria in the lag phase were exposed to an in vitro gentamicin concentration series which mirrored the concentrations determined in patients after 80-mg intravenous bolus (1 min) and 80-mg intravenous infusion (30 min) doses. Bacterial viable cell counts and gentamicin concentrations were measured before and during antibiotic exposure. Both the Cmax and AUC were shown to be factors determining antibacterial activity; however, the Cmax was an independent determinant of effect. These findings indicate that bolus intravenous dosing with gentamicin could maximize bactericidal activity. Increased efficacy could result at any given daily antibiotic dose if delivered via bolus with long intervals (12 to 24 h) between doses if appropriate precautions to avoid toxicity are taken.Antibiotic therapeutic effect depends on administration schedules (6,7,20) and the time course of antibiotic concentration in serum, including the area under the antibiotic concentration in plasma-time curve (AUC), the magnitude of the AUC above the MIC (AUC > MIC), the total time that the antibiotic concentration exceeds the MIC, and the maximum antibiotic concentration attained during a dosing interval (Cm,[) (2, 7-10, 13, 14, 22).The issue of Cmax as opposed to AUC as a major determinant of antibiotic activity is of critical importance for dosage design; however, this issue has not yet been definitely resolved (16,22). We report the results of studies designed to test the independent effects of Cmn and AUC of gentamicin on bactericidal effect.Preliminary data were presented to the Australian Society of Clinical and Experimental Pharmacologists and Toxicologists, December 1991.Pharmacokinetic studies involved 20 patients on chronic 8-h dosing regimens with gentamicin at 80 mg; the regimen consisted of a standard 30-min infusion or a bolus over 1 min. Blood samples were drawn predose and at 1, 20, and 30 min postdose. A 10-min postdose in vivo datum point was estimated from a first-order fit of the 0-to 30-min in vivo data.Escherichia coli NCTC 10418 was used in in vitro bactericidal experiments. Both the MIC and the MBC of gentamicin for this organism are 0.5 mg/liter. This organism was cultured under standard conditions in the presence and absence of gentamicin (Delta West, Bentleigh, Australia) as detailed below. An overnight culture of E. coli in brain heart infusion broth (BHIB) (Oxoid, Basingstoke, England) was diluted to 107 CFU/ml in 0.1% peptone water (Difco Laboratories, Detroit, Mich.). A 1-ml sample of the 107-CFU/ml * Corresponding author. culture was added to the experimental culture broth, resulting in an initial density of 106 CFU/ml.In vitro concentration-time modelling of clinical concentrations of gentamicin assumed linear extrapolation of in vivo data (Fig. 1). Bolus and infusion profiles based on these findings at tw...

Background -There is evidence that administration of higher doses of aminoglycosides given less frequently improves the bactericidal effect and reduces the potential to cause side effects. To investigate this, a prospectively randomised open label therapeutic trial was undertaken in stratified groups of patients with cystic fibrosis to examine the efficacy and toxic potential of an aminoglycoside dosing regimen designed to generate high peak drug concentrations at 12 hourly intervals compared with conventional dosing at eight hourly intervals. Methods -Patients in group A received tobramycin eight hourly using a dose aimed at generating a peak concentration of 10 mgIl with trough concentrations below 2 mglI, and those in group B received the total daily dose required to achieve eight hourly target concentrations administered as two equal 12 hourly doses. Clinical outcomes measured and assessed included vestibular symptoms, hearing and renal function, length of hospital stay, readmission rate, and mortality. Results -Twenty nine patients were recruited during a six month period, 20 to group A and nine to group B. The average peak tobramycin level was higher in group B (12.5 (2.2) mgIl) than in group A (7.9 (1.9) mgIl), whilst the average trough level was higher in group A (0-8 (0.3) mgIl) than in group B (0-5 (0.2) mg/l). There was a difference in the number ofototoxic events between patients in group A (seven of 18, 38c9%) and group B (none of eight), but no difference was found in other outcome measures assessed. Conclusions -These results suggest that 12 hourly high peak aminoglycoside dosing may be less toxic than equivalent eight hourly dosing, without any apparent difference in efficacy. (Thorax 1996;51:369-373) Keywords: aminoglycosides, cystic fibrosis, ototoxicity.Aminoglycoside antibiotics provide an effective and inexpensive treatment for Gram negative infections, yet their usefulness as antibiotics has been limited by their potential to cause ototoxicity and nephrotoxicity. }6ere is evidence from both human and animal models that larger doses of aminoglycosides given less frequently reduce their potential to cause such side effects.4"'7 The efficacy of larger less frequent aminoglycoside dosing regimens becomes a concern in patient groups whose clearance of the drug makes the interdose interval more critical, and these patient groups must be included in any rational analysis of this issue. Patients with cystic fibrosis represent such a group.The primary pathogens implicated in the chronic lung infection associated with cystic fibrosis are Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa, the latter being responsible for chronic infection in 70-90% of all these patients.""24 P aeruginosa undergoes phenotypic adaptation within the lungs of patients with cystic fibrosis, the most important being the emergence of mucoid strains. The aim of this study was to examine the efficacy and toxic potential of a dosing regimen oftobramycin which generate...

A study was made of the influence of peak gentamicin concentration (Cmax) independent of the area under the antibiotic concentration-time curve (AUC) on the bactericidal effect of gentamicin against Escherichia coli NCTC 10418. Bacteria in the lag phase were exposed to in-vitro gentamicin concentration-time profiles which modelled complete profiles determined in vivo in patients after an intravenous bolus (1 min) or infusion (30 min) regimen. An additional in-vitro profile reflected antibiotic removal 30 min after bolus dosing. Bacterial viable cell counts and gentamicin concentrations were measured before and during antibiotic exposure. Both Cmax and AUC were shown to be factors determining antibacterial activity; however Cmax independently represented some 35% of total exposure effect. These findings indicate grounds for preferring bolus intravenous gentamicin dosing with appropriate attention to potential toxicity.