Single daily dosing of antibiotics: importance of in vitro killing rate, serum half-life, and protein binding

Abstract

The relative importance of pharmacokinetic and pharmacodynamic parameters for the feasibility of a single daily dose (SDD) of antibiotics remains to be established. Therefore, we studied the relationship between in vitro bacteriological parameters (MIC, MBC, and killing rate [KR], defined as the reduction in the inoculum within 3 h), pharmacokinetic parameters (t1/2 and protein binding [PB]), and the in vivo antibacterial effect of a single antibiotic dose in an experimental rabbit model of Escherichia coli endocarditis. Nine antibiotics were investigated: two aminoglycosides, two quinolones, and five I-lactams. For each drug, the minimal effective dose (MED) (in milligrams per kilogram) was defined as the lowest dose able to achieve a significant difference (P < 0.05) of CFU in the vegetations in comparison with controls 24 h after a single intravenous injection.Aminoglycosides and quinolones had the lowest MEDs, followed by ,-lactams. Univariate regression analysis showed that KR was the major determinant of MED. A stepwise regression analysis showed that t1/2 significantly improved the predictive value of KR, while PB, MIC, and MBC did not. The final equation was MED = 1,586 -238 KR -27 t1/2 (r = 0.90, P = 0.01). We concluded that the pharmacodynamic parameters (especially the high KR) of aminoglycosides and quinolones explained their low MEDs and might allow SDD.In contrast, the low KR of P-lactams emphasized the critical importance of a long 412, as for ceftriaxone, allowing the use of this ,I-lactam alone in SDD.Single daily dosing of antibiotics appears to be a promising way to lighten therapy, reducing the work load for the nursing staff and inconvenience for the patient. For some drugs, such as aminoglycosides, efficacy and tolerance of single daily dosing have been demonstrated in different animal models (1,11,18) and in humans (20,21,28), despite their very short half-lives. This indicates that factors other than kinetic parameters play a major role in vivo in the feasibility of single daily doses. These factors include pharmacodynamic parameters, such as the dose-effect relationship (12,19), and the presence of a postantibiotic effect (16). The conclusions of different studies suggest that some antibiotics, for example ,B-lactams, are mainly time-dependent, i.e., those with short half-lives are probably not suitable for single daily dosing (23), whereas others, such as aminoglycosides, are mainly concentration-dependent, i.e., single daily dosing is more effective than the same daily dose given in multiple injections (13). Thus, it appears that pharmacokinetic parameters, such as t1,2, do not have the same influence on dosing interval, depending upon the antibiotic's bactericidal activity (i.e., time-dependent or concentrationdependent antibacterial activity). Furthermore, the killing rate (KR), determined in vitro by time-kill curves, might predict the bacteriological outcome of a treatment better than MIC or MBC. This point was underlined in a clinical study (9).The aim of this study was to identif...

Identification of factors affecting in vivo aminoglycoside activity in an experimental model of gram-negative endocarditis

“…bolus injection (48 mg/kg) on the two strains (E474 and E475) could have been related to the higher killing rate in vitro (expressed as the ISB) of these two drugs for strain E475 than for strain E474. This result is in agreement with that of a previous study (23), in which a good correlation was demonstrated between the in vitro killing rate and the in vivo effect of a single dose of antibiotic in an E. coli endocarditis model. Similarly, the better in vitro activity of gentamicin than of tobramycin or amikacin on the strain of S. marcescens was probably responsible for the low MED of the former compound (48 mg/kg for gentamicin versus 72 mg/kg for amikacin and tobramycin).…”

“…We tried to confirm the importance of the in vitro killing rate in the efficacy of a single i.v. bolus dose, as previously shown in the same model of E. coli endocarditis (23). The second parameter which was investigated was the critical serum drug concentration (CSC, in milligrams per liter), defined as the lowest serum antibiotic concentration able to achieve significant in vivo bactericidal activity 24 h after the beginning of a continuous i.v.…”

Experimental Streptococcus pneumoniae infection in mice for studying correlation of in vitro and in vivo activities of penicillin against pneumococci with various susceptibilities to penicillin

“…The concept of studying the pharmacodynamics, i.e., the correlation of the effect in vivo with the pharmacokinetics, in experimental models with several different bacteria with various susceptibilities to the antibiotics in question has been attempted by several investigators (2,5,11,16,28,32,35). If different bacteria are used, the question arises as to whether the infections caused by bacteria with different virulence properties and, possibly, the different immune responses elicited by the host can provide any meaningful insight into the pharmacodynamic properties of different antibiotics with different modes of action (2,11,35).…”

Pharmacokinetic and pharmacodynamic requirements for antibiotic therapy of experimental endocarditis

“…Most of these conclusions regarding the relation between the pharmacodynamics of antibiotics and optimal dosage have been verified in experimental bacterial endocarditis (9,36,39,50,51,55).…”