The nephrotoxicity and ototoxicity associated with once-daily versus twice-daily administration of aminoglycosides was assessed in patients with suspected or proven gram-negative bacterial infections in a randomized, double-blind clinical trial. Patients who received therapy for ≥72 h were evaluated for toxicity. Patients also received concomitant antibiotics as deemed necessary for treatment of their infection. Plasma aminoglycoside concentrations, prospective aminoglycoside dosage adjustment, and serial audiologic and renal status evaluations were performed. The probability of occurrence of a nephrotoxic event and its relationship to doses and daily aminoglycoside exposure served as the main outcome measurement. One hundred twenty-three patients were enrolled in the study, with 83 patients receiving therapy for at least 72 h. For 74 patients plasma aminoglycoside concentrations were available for analysis, and the patients formed the group evaluable for toxicity. The primary infectious diagnosis for the patients who were enrolled in the study were bacteremia or sepsis, respiratory infections, skin and soft tissue infections, or urosepsis or pyelonephritis. Of the 74 patients evaluable for toxicity, 39 received doses twice daily and 35 received doses once daily and a placebo 12 h later. Nephrotoxicity occurred in 6 of 39 (15.4%) patients who received aminoglycosides twice daily and 0 of 35 patients who received aminoglycosides once daily. The schedule of aminoglycoside administration, concomitant use of vancomycin, and daily area under the plasma concentration-time curve (AUC) for the aminoglycosides were found to be significant predictors of nephrotoxicity by multivariate logistic regression analysis (P ≤ 0.001). The time to a nephrotoxic event was significantly influenced by vancomycin use and the schedule of administration, as assessed by Cox proportional hazards modeling (P ≤ 0.002). The results of the multivariate logistic regression analysis and the Cox proportional hazards modeling demonstrate that both the probability of occurrence and the time to occurrence of aminoglycoside nephrotoxicity are influenced by the schedule on which the aminoglycoside is administered as well as by the concomitant use of vancomycin. Furthermore, this risk of occurrence is modulated by the daily AUC for aminoglycoside exposure. These data suggest that once-daily administration of aminoglycosides has a predictably lower probability of causing nephrotoxicity than twice-daily administration.

We adapted an in vitro pharmacodynamic model of infection to incorporate simulated endocardial vegetations. The bactericidal activities of teicoplanin, vancomycin, gentamicin, and various combinations of these drugs were studied against a strain of methicillin-susceptible Staphylococcus aureus obtained from a patient being treated for endocarditis at Detroit Receiving Hospital. Bacteria were grown overnight, concentrated, and added to a mixture of cryoprecipitate (80%o)

The aggregation of amyloid beta (Ab)p roteins in senile plaques is ac ritical event during the development of Alzheimersdisease,and the postmortem detection of Ab-rich proteinaceous deposits through fluorescent staining remains one of the most robust diagnostic tools.I na nimal models, fluorescence imaging can be employed to follow the progression of the disease,and among the different imaging methods, two-photon microscopy(TPM) has emerged as one of the most powerful. To date,s everal near-infrared-emissive two-photon dyes with ahigh affinity for Ab fibrils have been developed, but there has often been at radeoff between excellent two-photon cross-sections and large fluorescence signal-to-background ratios.I nt he current work, we introduced at wisted intramolecular charge state (TICT)-based de-excitation pathway, which results in aremarkable fluorescence increase of around 167-fold in the presence of Ab fibrils,w hile maintaining an excellent two-photon cross section, thereby enabling highcontrast ex vivo and in vivo TPM imaging. Overall, the results suggest that adopting TICT de-excitation in two-photon fluorophores may represent ag eneral method to overcome the tradeoff between probe brightness and signal-to-background ratio.

We compared the pharmacodynamics and killing activity of ceftazidime, administered by continuous infusion and intermittent bolus, against Pseudomonas aeruginosa ATCC 27853 and ceftazidime-resistant P. aeruginosa 27853CR with and without a single daily dose of amikacin in an in vitro infection model over a 48-h period. Resistance to ceftazidime was selected for by serial passage of P. aeruginosa onto agar containing increasing concentrations of ceftazidime. Human pharmacokinetics and dosages were simulated as follows: half-life, 2 h; intermittent-bolus ceftazidime, 2 g every 8 h (q8h) and q12h; continuous infusion, 2-g loading dose and maintenance infusions of 5, 10, and 20 g/ml; amikacin, 15 mg/kg q24h. There was no significant difference in time to 99.9% killing between any of the monotherapy regimens or between any combination regimen against ceftazidime-susceptible P. aeruginosa. Continuous infusions of 10 and 20 g/ml killed as effectively as an intermittent bolus of 2 g q12h and q8h, respectively. Continuous infusion of 20 g/ml and an intermittent bolus of 2 g q8h were the only regimens which prevented organism regrowth at 48 h, while a continuous infusion of 5 g/ml resulted in the most regrowth. All of the combination regimens exhibited a synergistic response, with rapid killing of ceftazidime-susceptible P. aeruginosa and no regrowth. Against ceftazidime-resistant P. aeruginosa, none of the ceftazidime monotherapy regimens achieved 99.9% killing. The combination regimens exhibited the same rapid killing of the resistant strain as occurred with the susceptible strain; however, regrowth occurred with all regimens. The combination regimens of continuous infusion of 20 g/ml plus amikacin and intermittent bolus q8h or q12h plus amikacin continued to be synergistic. Overall, continuous infusion monotherapy with ceftazidime at concentrations 4 to 5 and 10 to 15 times the MIC was as effective as an intermittent bolus of 2 g q12h (10 to 15 times the MIC) and q8h (25 to 35 times the MIC), respectively, against ceftazidime-susceptible P. aeruginosa. Combination therapy with amikacin plus ceftazidime, either intermittently q8h or by continuous infusion of 20 g/ml, appeared to be effective and exhibited synergism against ceftazidime-resistant P. aeruginosa.

Cefepime (CP) is a new injectable cephalosporin with a broad spectrum of activity and stability against common chromosomally and plasmid-mediated ␤-lactamases. The bactericidal activities of CP, ceftazidime (CZ), cefotaxime (CTX), and ceftriaxone (CAX) against reference and clinical strains of Staphylococcus aureus, an isogenic pair of Enterobacter aerogenes strains (wild type and a CZ-resistant derepressed mutant), and a Klebsiella pneumoniae isolate possessing a TEM-10 ␤-lactamase were investigated in a two-compartment pharmacodynamic in vitro infection model which simulates human pharmacokinetics. An inoculum of ϳ10 6 CFU/ml was used in all model experiments. Antibiotics were administered to simulate the following regimens: CP at 2 g every 12 h (q12h), CZ at 2 g q8h, CTX at 2 g q8h, and CAX at 2 g q24h. Human albumin was added during experiments with CAX and staphylococci to simulate protein binding. Samples were removed at multiple time points over a 48-h period to determine the inoculum size for time-kill curves. Development of resistance was detected by inoculating samples obtained at 0, 24, and 48 h onto antibiotic-containing agar plates. The time to 99.9% killing was used to compare drug regimens. Against staphylococci, the time to bacterial eradication was significantly delayed with CAX-albumin. All regimens had similar activities against the wild-type Enterobacter strain; however, regrowth was noted with CZ, CTX, and CAX against the CZresistant strain. There were no differences between the CP, CTX, and CAX regimens against K. pneumoniae. Of interest, no regrowth of any organism was noted with CP. These data indicate that CP has activity against S. aureus and CZ-resistant gram-negative bacilli.Cefepime is a new injectable cephalosporin with a broad spectrum of activity against many gram-positive and gramnegative bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa. It has poor affinity for inducible chromosomally mediated cephalosporinases (Bush group 1) and is resistant to hydrolysis by most common chromosomally and plasmid-mediated enzymes, including the recently described extended-broad-spectrum ␤-lactamases of the Bush 2bЈ classification (4, 5). In vitro data indicate that cefepime retains activity against gram-negative organisms which have developed resistance to other broad-spectrum cephalosporins and thus may be useful for the treatment of infections involving these bacteria. Like other broad-spectrum cephalosporins, cefepime will probably be used empirically in patients for whom the infecting pathogen has not yet been identified. Therefore, activity against gram positive organisms that is comparable to those of other commonly used agents will be necessary. The purpose of this investigation was to compare the bactericidal activity of cefepime with those of ceftazidime, cefotaxime, and ceftriaxone against S. aureus and ␤-lactamase-producing strains of Enterobacter aerogenes and Klebsiella pneumoniae. MATERIALS AND METHODSBacterial strains. Two strains of methicillin-sensitive S. au...