Once-daily aminoglycoside (ODA) regimens have been instituted to maximize bacterial killing by optimizing the peak concentration/MIC ratio and to reduce the potential for toxicity. We initiated an ODA program at our institution that utilizes a fixed 7-mg/kg intravenous dose with a drug administration interval based on estimated creatinine clearance: Ն60 ml/min every 24 h (q24h), 59 to 40 ml/min q36h, and 39 to 20 ml/min q48h. Subsequent interval adjustments are made by using a single concentration in serum and a nomogram designed for monitoring of ODA therapy. Since initiation of the program, 2,184 patients have received this ODA regimen. The median dose was 450 (range, 200 to 925) mg, while the median length of therapy was 3 (range, 1 to 26) days. The median age of the population was 46 (range, 13 to 97) years. Gentamicin accounted for 94% of the aminoglycoside use, and the majority (77%) of patients received the drug q24h. The 36-, 48-, and >48-h intervals were used for 15, 6, and 2% of this population, respectively. Three patients exhibited clinically apparent ototoxicity. Twenty-seven patients (1.2%) developed nephrotoxicity (the Hartford Hospital historical rate is approximately 3 to 5%) after a median of 7 (range, 3 to 19) days of therapy. On the basis of a prospective evaluation of 58 patients and follow-up of additional patients via clinician reports, we have noted no apparent alterations in clinical response with our ODA program. This ODA program appears to be clinically effective, reduces the incidence of nephrotoxicity, and provides a cost-effective method for administration of aminoglycosides by reducing ancillary service time and serum aminoglycoside determinations.
Continuous infusion of piperacillin-tazobactam provided clinical and microbiologic outcomes equivalent to those for intermittent infusion. Compared with intermittent infusion, continuous infusion significantly shortened the time to temperature normalization, while also offering a significant reduction in level 2 expenditures.
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.Although aminoglycoside antibiotics have been used sucat the binding site for a finite period of time [5]. The presence cessfully for ú50 years [1], recent data suggest that the convenof the antibiotic prohibits normal biochemical reactions and, tional dosing approach has not optimized bacterial killing. therefore, the organism dies. The concentration needed to ocThese recent observations, together with a more complete uncupy the critical number of sites necessary for this to occur is derstanding of pharmacodynamics, have led to the application not known. However, an easily measured and probably proporof new aminoglycoside dosing regimens [2, 3]. In this report tional concentration, such as the MIC or the MBC, is used in we discuss the pharmacodynamics of aminoglycosides and the its place. new dosing strategies for this class of antibiotics.It is also important to realize that the concentration of drug The in vitro antimicrobial spectrum of activity of the aminoin the area of binding sites is controlled by drug concentration glycosides includes a broad range of aerobic gram-negative in the media in which bacteria reside, usually interstitial-like bacilli, many staphylococci, and certain mycobacteria [4].fluid. Antibiotics in such fluids have generally been found to Aminoglycosides exert their bactericidal effects by irreversibly rapidly become in equilibrium with the blood; therefore, antibibinding to the 30S ribosomal subunit of susceptible bacteria, otic blood (serum, plasma) concentrations are an important which results in the inhibition of protein synthesis [4]. An parameter in bactericidal activity. Bactericidal activity is thereenergy-and oxygen-dependent transport mechanism is required fore a function of antibiotic concentration in the serum and the for aminoglycosides to penetrate the outer bacterial membrane duration of time that antibiotic exists in the body. of susceptible bacteria [4]. It is for this reason that this classIn pharmacodynamic terms, one can say that bactericidal of antibiotics demonstrates poor activity against anaerobes and activity is a function of the time that serum concentrations has decreased ability to penetrate the bacteria within abscesses remain above some critical value, i.e., the MIC. Pharmacokinetthat may have limited oxygen.ically, the product of concentration and time is termed the area In general, the aminoglycosides are clinically used in the under the serum-time curve (AUC), and therefore it i...
Enterococcus faecalis produces a specific penicillin-binding protein (PBP5) that mediates high-level resistance to the cephalosporin class of -lactam antibiotics. Deletion of a locus encoding a previously uncharacterized two-component regulatory system of E. faecalis (croRS) led to a 4,000-fold reduction in the MIC of the expanded-spectrum cephalosporin ceftriaxone. The cytoplasmic domain of the sensor kinase (CroS) was purified and shown to catalyze ATP-dependent autophosphorylation followed by transfer of the phosphate to the mated response regulator (CroR). The croR and croS genes were cotranscribed from a promoter (croRp) located in the rrnC-croR intergenic region. A putative seryl-tRNA synthetase gene (serS) located immediately downstream from croS did not appear to be a target of CroRS regulation or to play a role in ceftriaxone resistance. A plasmid-borne croRp-lacZ fusion was trans-activated by the CroRS system in response to the presence of ceftriaxone in the culture medium. The fusion was also induced by representatives of other classes of -lactam antibiotics and by inhibitors of early and late steps of peptidoglycan synthesis. The croRS null mutant produced PBP5, and expression of an additional copy of pbp5 under the control of a heterologous promoter did not restore ceftriaxone resistance. Deletion of croRS was not associated with any defect in the synthesis of the nucleotide precursor UDP-MurNAc-pentapeptide or of the D-Ala 4 3L-Ala-L-Ala-Lys 3 peptidoglycan cross-bridge. Thus, the croRS mutant was susceptible to ceftriaxone despite the production of PBP5 and the synthesis of wild-type peptidoglycan precursors. These observations constitute the first description of regulatory genes essential for PBP5-mediated -lactam resistance in enterococci.Enterococcus faecalis and E. faecium are opportunistic pathogens that are common causes of urinary tract infections, bacteremia, and endocarditis (20). Enterococcal infections are difficult to treat, as enterococci are intrinsically resistant to various antibiotics and can acquire, mainly by horizontal gene transfer, high-level resistance to virtually all antimicrobial agents. The complete genome sequence of E. faecalis strain V583 revealed an unusually high (25%) content of mobile elements and exogenously acquired DNA, including virulence factors and antibiotic resistance genes (22). The plasticity of the genome correlates with the facility of enterococci to acquire novel resistance mechanisms and to transfer the corresponding genes to other genera, as exemplified by the emergence of high-level glycopeptide resistance in E. faecalis and E. faecium in the late 1980s and the dissemination of the same gene cluster in Staphylococcus aureus 15 years later (8).Enterococci are resistant to the newer cephalosporins which have been developed to treat infections due to gram-negative bacteria producing -lactamases. Treatment with cephalosporins is one of the risk factors for colonization and infection by multidrug-resistant enterococci. Cephalosporin resistance is me...
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