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To identify the optimal pharmacodynamic exposures of meropenem, imipenem, and cefepime, and the emergence of resistance in vivo for Pseudomonas aeruginosa overexpressing MexA-MexB-OprM efflux pumps, we used the murine thigh model. Mice were challenged with P. aeruginosa isolates: PAO1 (K767 wild type), K767+ (MexA-MexB-OprM efflux mutant), and DeltaK767 (knockout strain). Efficacy (Delta log colony-forming unit [CFU]) was determined at various exposures of %T > MIC at both standard (10(5) CFU/thigh) and high (10(7) CFU/thigh) inoculums. At 10(5) CFU/thigh, meropenem and imipenem produced a maximal activity against PAO1 (-2.82, -1.88) and K767+ (-2.24, -2.68) at 40%T > MIC; cefepime at 70%T > MIC produced a comparable kill (-2.74 and -2.19, respectively). Similar magnitudes of kill were observed at the 10(7) inocula. Except for DeltaK767 with cefepime, no development of resistance emerged at various %T > MIC. All agents exhibited reduced activity against DeltaK767. DeltaK767 cefepime-resistant strains were isolated up to 100%T > MIC. The overexpression of MexA-MexB-OprM efflux pumps did not result in the loss of efficacy of the antibiotics tested regardless of the amount of bacterial inocula; however, their presence also did not lead to increased selection for resistance. The effects of efflux mechanisms on beta-lactam agents in vivo warrant further research.

Objectives.To evaluate the economic and clinical impact of infection with extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella species (ESBL-EK).Design.A matched-cohort analysis of the cost of illness.Setting.An 810-bed, urban, community hospital in Hartford, Connecticut.Patients.Twenty-one case patients infected with ESBL-EK at a site other than the urinary tract were matched with 21 control subjects infected with a non–ESBL-producing organism on the basis of pathogen species, age, anatomic site of infection, hospitalization in the intensive care unit (ICU) during the time of infection, date of hospitalization, and initial antibiotics received.Results.Mean infection-related costs per patient were significantly greater for case patients than for control patients ($41,353 vs $24,902; P = .034). Infection-related length of stay was the main driver of cost, which was prolonged for case patients, compared with control patients (21 vs 11 days; mean difference, 9.7 days [95% confidence interval {CI}, 3.2-14.6 days] P = .006). The additional cost attributed to the presence of an ESBL-EK infection was $16,450 per patient (95% CI, $965-$31,937). Case patients were more likely than control patients to have clinical failure (P = .027), and the rate of treatment success for case patients whose initial treatment involved antibiotics other than carbapenems was lower than that for their matched control patients (39% vs 83%; P = .013). Treatment was successful in patients for whom initial treatment was with a carbapenem, regardless of the ESBL status of the pathogen.Conclusion.The cost of non–urinary tract infections caused by ESBL-EK was 1.7 times the cost of non–urinary tract infections caused by non-ESBL producers. Prompt recognition and appropriate antimicrobial selection may minimize this ESBL-related impact on hospital costs.

The objectives of this study were to develop a meropenem population pharmacokinetic model using patient data and use it to explore alternative dosage regimens that could optimize the currently used dosing regimen to achieve higher likelihood of pharmacodynamic exposure against pathogenic bacteria. We gathered concentration data from 79 patients (ages 18-93 years) who received meropenem 0.5, 1, or 2 g over 0.5- or 3-hour infusion every 8 hours. Meropenem population pharmacokinetic analysis was performed using the NONMEM program. A 2-compartment model fit the data best. Creatinine clearance, age, and body weight were the most significant covariates to affect meropenem pharmacokinetics. Monte Carlo simulation was applied to mimic the concentration-time profiles while 1 g meropenem was administrated via infusion over 0.5, 1, 2, and 3 hours. The 3-hour prolonged infusion improved the likelihood of obtaining both bacteriostatic and bactericidal exposures most notably at the current susceptibility breakpoints.

Gallbladder cancer is an asymptomatic disease in the early stage and no therapeutic measure is available except surgical intervention. The prognosis for patients with advanced,i.e., unresectable or metastatic disease is dismal, with median survival usually being less than 6 months if not treated with chemotherapy. To date, chemotherapy for gallbladder cancer has been limited by the absence of agents with effective cytotoxic activity. Thalidomide has been shown to have antiangiogenic and immunomodulatory effects, including the inhibition of vascular endothelial growth factor, basic fibroblast growth factor and tumor necrosis factor alpha. Celecoxib is a potent selective COX-2 inhibitor. The reported biological consequences of COX-2 up-regulation include inhibition of apoptosis, increased metastatic potential and promotion of angiogenesis. These events may contribute to cell transformation and tumor progression. Antiangiogenesis represents a significant new strategy for cancer treatment. Therefore,it is important to accept a wide range of different inhibitors such as thalidomide and selective COX-2 inhibitors with conventional cytotoxic agents. Here we show a case of unresectable gallbladder cancer with remarkable improvement in CA19-9 and prolongation of life.

Objective To determine the affect of ESBL production among Klebsiella species and Escherichia coli on cefepime effectiveness. Methods This was a retrospective, case–controlled study comparing the clinical and microbiologic responses of patients receiving cefepime for ESBL producing Klebsiella species or E. coli from a non-urine source with matched controls receiving cefepime for non-ESBL strains. Cases with ESBLs were included if they received monotherapy and were clinically evaluable. Non-ESBL controls were matched in a 2:1 ratio based on age, infection site, intensive care unit (ICU) stay, pathogen species and date of hospitalization. Results Ten patients receiving cefepime for ESBLs were matched to 20 controls. Most patients received cefepime 1g q12h. Patients receiving cefepime for an ESBL infection were 9.7 (95% CI: 1.4–68.8) and 28.5 (95% CI: 2.6–306.6) times as likely to have an unsuccessful clinical and microbiological response compared with those with a non-ESBL infection. The presence of an ESBL did not have a statistically significant effect on all cause or infection-related mortality. Conclusion These data indicate that ESBL production among non-urinary Klebsiella species and E. coli negatively affected cefepime effectiveness. Further studies are required to evaluate if higher doses of cefepime may improve responses in ESBLs that are initially susceptible.

OBJECTIVES We investigated the population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam in hospitalized patients. PATIENTS AND METHODS A multicentre, randomized clinical trial was conducted in hospitalized patients with complicated intra-abdominal infection. Patients received piperacillin/tazobactam administered by either continuous infusion (13.5 g over 24 h, n = 130) or intermittent infusion (3.375 g every 6 h, n = 132). NONMEM was used to perform population pharmacokinetic analysis in a subset of patients (n = 56) who had serum samples obtained at steady-state for drug concentration analyses. Classification and regression tree analysis was used to identify the breakpoints of piperacillin PK-PD indexes in 94 patients with causative pathogen's MIC. RESULTS A one-compartment model was applied to fit the data. Creatinine clearance and body weight were the most significant variables to explain patient variability in piperacillin and tazobactam clearance and volume of distribution. The infusion method had no influence on PK parameters. For patients (n = 30) receiving intermittent infusion in the pharmacokinetic study, mean Cmax and half-life were 122.22 mg/L and 1.17 h for piperacillin, and 15.74 mg/L and 1.81 h for tazobactam. For patients (n = 26) receiving continuous infusion in the pharmacokinetic study, mean steady-state concentration was 35.31 +/- 12.15 mg/L for piperacillin and 7.29 +/- 3.28 mg/L for tazobactam. As a result of a low rate of failures (

Study Objective. To compare the pharmacodynamics of two β-lactams—ceftazidime and meropenem—in healthy subjects versus patients. Design. Monte Carlo simulation based on published pharmacokinetic studies. Subjects. One hundred and ninety-seven participants (75 healthy volunteers and 122 patients) from published pharmacokinetic studies of ceftazidime or meropenem. Measurements and Main Results. Data on total body clearance and volume of distribution for ceftazidime and meropenem in healthy subjects and patients were obtained from published studies. Monte Carlo simulations were performed based on the pharmacokinetics from each study for ceftazidime 1000 mg every 8 hours and meropenem 1000 mg every 8 hours against isolates of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa collected from North and South America. We calculated the likelihood of obtaining bactericidal exposures (50% time above the minimum inhibitory concentration [MIC] for ceftazidime and 40% time above the MIC for meropenem) for each combination of pharmacokinetic study data and MIC distribution. Linear regression was used to compare target attainments for healthy subjects versus patients. Only three drug-pathogen combinations differed in target attainment between healthy subjects and patients: ceftazidime against P. aeruginosa in North America and meropenem against E. coli and P. aeruginosa in South America. The regression line of target attainment for patients versus healthy subjects had a slope of 1.04 (95% confidence interval [CI] 0.983–1.093) and a y intercept of −3.73 (95% CI −8.265–0.827, r2 = 0.992). The 0 values for slope and intercept did not differ to a statistically significant extent between the regression line and the line of identity (p=0.264). Conclusion. The pharmacodynamic target attainment calculated with healthy subject pharmacokinetic data was predictive of patient target attainment for ceftazidime and meropenem.

Telithromycin (TEL) is a ketolide antimicrobial agent with in vitro activity against Streptococcus pneumoniae (SPN), including macrolide resistant strains. The purpose of this study was to assess the efficacy of TEL against clinical SPN isolates with various genotypic mutations including the newly recognized ribosomal mutations. Pneumonia was induced in either immunocompetent and immunosuppressed mice. Six isolates were included in the study and all were resistant to azithromycin (AZI) by MIC testing. Three oral regimens of TEL were chosen to simulate the human pharmacokinetic (PK) exposures observed in young healthy, healthy elderly (≥65 years), and infected subjects. An additional group was given AZI in human simulated doses. Bacterial density in lung was determined after each treatment. Telithromycin administered simulating infected patients showed greater efficacy (i.e., change in log CFU) than the azithromycin treated group for all isolates except P1660008. The immune system was responsible for increased efficacy (ranging from 45–146%) for all but one of the telithromycin treatment regimens. Unlike other isolates studied in this in vivo model, P1660008 displayed a highly variable response to therapy, such that the reductions in CFU were not consistent with the microbiological and PK profiles of either compound. For all other isolates, the activity of AZI was comparable with untreated controls. Human simulated exposures of TEL displayed 0.5–3.4 log kill in vivo despite the ribosomal mutations studied. These data support the in vivo efficacy of TEL against a variety of genotypic resistance profiles observed in pneumococci, however, additional studies are required to fully characterize the killing profile of the compound against these recently determined ribosomal mutations.

Objective: This study compared the quality of 65 generic clarithromycin products manufactured in 18 countries with that of the innovator product. Design: To assess quality, the generic products were examined visually, assayed by high-pressure liquid chromatography for clarithromycin content and impurities, tested for dissolution properties, and compared with the innovator product manufactured by Abbott Laboratories. Results: This survey found that many generic clarithromycin products were not equivalent to the innovator product and many of these generic products fell short of the approved specifications developed for the innovator product. Overall, 9% (6 of 65) of all generic tablets tested failed to contain between 95% and 105% of the clarithromycin claimed in the label, thus falling short of the approved registered specification for the innovator product. Seventeen percent (1 of 6) of tablets from Latin America (LA), 8% (3 of 38) of tablets from the Asia, Africa, Pacific (AAP) region, and 10% (2 of 21) of tablets from Europe did not contain the amount of clarithromycin drug content claimed in the label. A total of 34% (17 of 50) of the generic products tested released less drug in 30 minutes than did the innovator tablets. Although the majority of these generic products met the dissolution specification requiring that 80% of the drug must dissolve in 30 minutes, one generic product failed to meet this specification with 68% of drug dissolving in 30 minutes. Moreover, 19% (12 of 65) of all the generic products tested exceeded the Abbott Laboratories’ 3% limit for total impurities in bulk drug, and 30% (20 of 65) exceeded the Abbott Laboratories’ 0.8% limit for the known impurity 6, 11 di-O-methyl erythromycin A. Conclusions: These results demonstrated that generic tablets are often not comparable in vitro to the innovator product. These findings suggest that results achieved with branded clarithromycin (Abbott Laboratories) should not be extrapolated to generic products. In vivo studies would be needed to determine the clinical relevance of these findings.

A simple and rapid assay is developed for the simultaneous analysis of piperacillin and tazobactam in rabbit serum and tissue cage fluid (TCF). To eliminate endogenous interferences, a wavelength switch technique was applied, in which the programmable UV detector changed the monitoring wavelength from 218 to 254 nm at 10 min. After liquid–liquid extraction, sample analyses were performed on a C18 column by gradient elution; the mobile phase consisted of acetonitrile and phosphate buffer (0.014 m, pH 2.4). Owing to the limited amount of rabbit TCF available, a cross-validation of a proxy matrix was evaluated. The relative standard deviation of the between- and within-batch precision of both compounds was less than 5.1%; the relative error of the between- and within-batch accuracy was less than 7.3%. The recoveries of both compounds in serum and TCF were larger than 80%. This assay was successfully applied to simultaneously analyze piperacillin and tazobactam in rabbit serum and TCF samples. Copyright © 2004 John Wiley & Sons, Ltd.

The new ketolide telithromycin has potent in vitro activity against Streptococcus pneumoniae , including strains resistant to penicillin, macrolides, and fluoroquinolones. The aim of the present study was to define the pharmacodynamic profile of telithromycin against S. pneumoniae strains with various resistance profiles in an in vivo system. Ten S. pneumoniae strains were studied; seven exhibited penicillin resistance, six demonstrated macrolide resistance, and two exhibited gatifloxacin resistance. The telithromycin MICs for all isolates were ≤0.5 μg/ml. Using the murine thigh infection model, CD-1/ICR mice were rendered neutropenic and were then inoculated with 10 5 to 10 6 CFU of S. pneumoniae per thigh. Telithromycin was administered orally at doses ranging from 25 to 800 mg/kg of body weight/day, with the doses administered one, two, three, or four times a day. The activity of telithromycin was assessed by determination of the change in the bacterial density in thigh tissue after 24 h of treatment for each treatment group and the untreated controls. Pharmacokinetic studies of telithromycin were conducted in infected, neutropenic animals. The levels of protein binding by telithromycin in mice ranged from 70 to 95% over the observed range of pharmacokinetic concentrations. By using either the total or the free concentrations of telithromycin, the area under the concentration-time curve (AUC)/MIC ratio was a strong determinant of the response against S. pneumoniae , regardless of the phenotypic resistance profile. The maximal efficacy (the 95% effective dose) against this cohort of S. pneumoniae strains and bacterial inhibition (stasis) of telithromycin were predicted by ratios of the AUC for the free drug concentration/MIC of approximately 1,000 and 200, respectively.

Purpose Despite the documented success of IV to oral anti-infective conversion programs, it is still unclear what the current standard of practice is in the US. A survey was conducted to evaluate the prevalence and characteristics of conversion programs throughout the nation. Methods A questionnaire was mailed to 890 randomly chosen hospital pharmacy directors. A preset cutoff date of 4 weeks from the initial mailing was set for responses; a second mailing was sent to those directors that did not respond initially. Results A total of 237 (27%) institutions responded. Of these, 74% had instituted conversion programs. More programs required prior physician notification compared with allowing pharmacists to proactively transition candidates (70% vs 30%, P < 0.001). The most common anti-infectives converted were the fluoroquinolones and fluconazole. Common conversion criteria included adequate oral intake and fever reduction. Characteristics associated with an increased likelihood of a conversion program were pharmacy residency programs (RR 1.3; 95% CI 1.132 to 1.477), clinical pharmacists (RR 1.6; 95% CI 1.262 to 2.123), ID specialty pharmacists (RR 1.3; 95% CI 1.153 to 1.499), ID physician consult service (RR 1.2; 95% CI 1.028 to 1.459), and teaching hospitals (RR 1.2; 95% CI 1.038 to 1.386). Hospitals with conversion programs employed a greater number of clinical pharmacists (P = 0.02). Multivariate analysis revealed that the presence of a clinical pharmacist was the most significant variable predicting implementation (P < 0.001). Conclusion The majority of hospitals responding to this survey had an intravenous to oral conversion program. While most programs still required prior physician notification, the presence of clinical pharmacists significantly influenced the prevalence of implementation and proactive transition.

To evaluate the adjunctive effect of interferon-gamma (IFN-gamma) in treatment of Pseudomonas aeruginosa pneumonia, neutropenic and non-neutropenic mice received LD(100) of the organism intratracheally, followed by subcutaneous administration of IFN-gamma, ceftazidime (TAZ) or a combination of both agents 2 h post-inoculation. Treatment with IFN-gamma alone showed no significant increase in survival when compared with control. Addition of IFN-gamma to TAZ resulted in no significant change in survival compared with TAZ alone. Survival in TAZ and TAZ + IFN-gamma groups, was significantly higher than in control and IFN-gamma groups. This suggests that adjunctive treatment with IFN-gamma in combination with ceftazidime may not be more beneficial than the antibiotic alone when managing acute P. aeruginosa pneumonia in both immunocompromised and immunocompetent hosts.

Cefepime was evaluated in vivo against two inoculum sizes of four strains of Escherichia coli that produced extended-spectrum beta-lactamases (ESBLs) in a murine neutropenic thigh infection model to characterize the pharmacodynamic activity of cefepime in the presence of ESBL-producing bacteria and to evaluate if differences in lengths of cefepime exposure are required with various inocula. Three strains possessed a single enzyme each: TEM-10, TEM-12, and TEM-26. The fourth strain possessed two TEM-derived ESBLs and a third uncharacterized enzyme. Two non-ESBL-producing E. coli strains were included for comparison. Mice received various doses of cefepime to achieve a spectrum of percentages of time the drug was above the MIC (% T >MICs) for each isolate at both inocula. No significant difference in cefepime exposure was required to achieve similar bactericidal effects for ESBL- and non-ESBL-producing isolates when the starting inoculum was 10 5 CFU of E. coli per thigh. The increased MICs observed in vitro for the ESBL-producing strains at 10 7 CFU/ml did not predict the amount of exposure required to achieve a comparable level of bactericidal activity in vivo at the corresponding starting inoculum of 10 7 CFU/thigh. Compared to the cefepime exposure in tests with the lower inoculum (10 5 CFU/thigh), less exposure was required when the starting inoculum was 10 7 CFU/thigh (% T >MIC, 6% versus 26%), such that similar doses (in milligrams per kilogram of body weight) produced similar bactericidal effects with both inocula of ESBL-producing isolates. Equivalent exposures of cefepime produced similar effects against the microorganisms regardless of the presence of ESBL production. Pharmacodynamic profiling undertaken with conventional cefepime MIC determinations predicted in vivo microbial outcomes at both inoculum sizes for the ESBL-producing isolates evaluated in this study. These data support the use of conventional MIC determinations in the pharmacodynamic assessment of cefepime.

As a result of macrolide resistance rates of 25% for pneumococci in the US, the clinical use of this class as empirical therapy has been questioned. However, macrolides continue to be used with clinical success. Using an immunocompromised murine pneumonia model, this study evaluated in vivo efficacy of human simulated exposures of clarithromycin for 62 isolates of Streptococcus pneumoniae considered resistant by current methods of breakpoint determinations. Changes in bacterial density were compared between treated animals and untreated controls. Inhibition of bacterial growth was consistently observed for the majority of isolates tested with mean (S.D.) reductions in logCFU per lung of -0.88 (0.69), -1.02 (0.87), -0.47 (0.79), -0.84 (0.66), -0.25 (0.26), -0.80 (0.72) and -0.58 (0.47) for MICs of 1, 2, 4, 8, 16, 32 and 64 mg/l, respectively. A beneficial treatment effect was clearly noted for isolates with clarithromycin MICs

Background: Meropenem is commonly used to treat lung infections in adults with cystic fibrosis (CF). Although continuous infusion is the ideal method to maximize the pharmacodynamic properties of this betalactam antibiotic, meropenem is stable for only ∼4 to 6 hours at room temperature, and its pharmacokinetic (PK) properties, when administered by continuous infusion to patients with CF, are largely unknown. Objective: This study was undertaken to determine the PK properties and stability of meropenem when administered to adults with CF by a continuous ambulatory drug-delivery infusion pump stored in a cold pouch between 2 freezer packs. Methods: This open-label, multidose, randomized, crossover PK study was conducted at the Clinical Research Center at Hartford Hospital (Harford, Connecticut). Adults aged ≥ 18 years with CF were eligible. Study participants were randomized to receive meropenem 125 mg/h or 250 mg/h (equivalent to 3 g and 6 g, respectively, over 24 hours) by continuous IV infusion for 12 hours. Serum samples were collected throughout the infusion and then for 6 hours after infusion to determine the PK properties (volume of distribution [V d ], elimination rate constant, total body clearance [CL], terminal half-life [t12], and steady-state concentration [C ss ]). Serum meropenem concentrations were assayed using high-performance liquid chromatography, and PK profiles were determined using compartmental analysis. Meropenem stability was ascertained by sampling the drug directly from the infusion pump at prespecified time points. Meropenem tolerability was assessed throughout the study by questioning subjects on how they felt. In addition, laboratory values of serum chemistries and liver enzymes were compared with baseline values. Results: Seven adult volunteers with CF (4 women, 3 men; mean [SD] age, 27 [10] years [range, 19–46 years]) participated in the study. Mean (SD) C ss values were 8.31 (0.68) mg/L and 18.50 (3.31) mg/L for the 125-mg/h and 250-mg/h infusion rates, respectively. V d , CL, and t12 were dose independent and similar between the 2 infusion rates. Meropenem stability was maintained over 12 and 24 hours. Meropenem by continuous infusion was well tolerated. One patient complained of a headache during the study. Conclusions: In this study of adults with CF, meropenem infusion rates of 125 mg/h and 250 mg/h provided serum drug concentrations greater than the minimum inhibitory concentration for pathogens considered meropenem susceptible (≤ 4 μg/mL) and intermediately resistant (8 μg/mL), respectively.

Recent clinical failures associated with levofloxacin treatment for Streptococcus pneumoniae infections and growing evidence of frequent mutations in the isolate population have led to increased concerns regarding fluoroquinolone resistance. Our objective was to characterize the efficacies of levofloxacin and moxifloxacin against various genotypes of S. pneumoniae after simulated bronchopulmonary exposures. An in vitro model was used to simulate a levofloxacin concentration of 500 mg and a moxifloxacin concentration of 400 mg, which were previously determined to be the concentrations in the epithelial lining fluid of older adults receiving once-daily dosing. The effects of the drugs were tested against six S. pneumoniae containing various mutations. Bacterial density and resistance were quantitatively assessed over 48 h. The S. pneumoniae isolate with no mutation displayed a 4-log reduction in CFU after treatment with both agents and did not develop resistance. Isolates containing the parC or parE mutation or both mutations regrew and developed resistance when they were exposed to levofloxacin, despite an unbound area under the concentration-time curve (AUC):MIC ratio of ∼100. When the isolate containing the parC and gyrA mutations was exposed to levofloxacin, there was a half-log reduction in the number of CFU compared to that for the control, but the isolate subsequently regrew. Likewise, levofloxacin did not kill the isolate containing the parC , gyrA , and parE mutations. Moxifloxacin sustained the killing of all bacterial isolates tested without the development of resistance. Levofloxacin did not sustain bacterial killing and did not prevent the emergence of further resistance in mutants with the parC or parE mutation or both mutations, even though an unbound AUC:MIC ratio for exposure well above the breakpoint of 30 to 40 established in the literature for S. pneumoniae was maintained. Moxifloxacin was effective against all isolates tested, despite the presence of isolates with two- and three-step mutations, for which the MICs were increased.

Background: Potential differences in toxicity, potency and acquisition price among the liposomal amphotericin B formulations makes it unclear which agent is less costly when total resource consumption and treatment-associated costs are considered. Design: A retrospective cost-minimisation analysis in 51 patients was performed to compare the cost of amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AMB) from the hospital perspective. Costs ($US, 2001 values) were divided into level I (acquisition price only), level II (costs of all associated treatment, i.e. adverse events, failures, etc.) and level III (total fungal-related hospitalisation) costs. Results: No significant differences in patient demographics or length of therapy were apparent among those receiving ABLC or L-AMB. The clinical success rate in this population was similar between ABLC and L-AMB (53% vs 60%, p = 0.68), thus justifying the use of a cost-minimisation analysis. Among patients with baseline elevations in serum creatinine, 47% receiving ABLC and 10% receiving L-AMB experienced further increases in serum creatinine (p = 0.025). No differences in total treatment costs (level I, II, or III) were evident between patients receiving ABLC or L-AMB. When adjusted for duration of therapy, however, costs were significantly lower for ABLC than for L-AMB (level I: ABLC $US340 versus L-AMB $US435, p = 0.002; level II: ABLC $US361 versus L-AMB $US454, p = 0.027). The costs attributable to the prevention or treatment of adverse events were not different between the two treatments, and the economic outcome in this analysis was highly sensitive to the acquisition price and dosage of the lipid antifungal formulation. Two-way sensitivity analysis revealed that as long as the milligram price of L-AMB was greater than 135% of the milligram price of ABLC, ABLC remained the less costly formulation. Conclusion: In this patient population, total hospitalisation costs were not different between lipid antifungal formulations. However, after controlling for duration of therapy, ABLC was less costly than L-AMB, when considering acquisition costs of the lipid antifungal agent and costs associated with concomitant antifungal therapy and the treatment of adverse events or lipid failures, indicating that the acquisition price of these agents should be predictive of their cost differences.

The efficacy of cethromycin was assessed against isolates of Streptococcus pneumoniae in the presence of neutrophils. Comparison with data from our previous neutropenic model revealed that the presence of neutrophils enhanced the bacteriostatic and bactericidal effect of cethromycin by an average of two- to four-times, respectively.

Study Objective. To assess the pharmacokinetics of meropenem administered as a 3-hour infusion. Design. Randomized, crossover, open-label study. Setting. Clinical research center. Subjects. Six healthy adult male volunteers. Intervention. Each subject received meropenem 0.5 or 2 g every 8 hours as a 3-hour infusion for three doses and then crossed over to the other dosage regimen. Measurement and Main Results. Pharmacokinetic parameters of both regimens were compared, and no significant differences between 0.5- and 2-g doses for the dose-independent parameters (half-life, clearance, and volume of distribution at steady state) were observed. The regimens displayed dose proportionality and were consistent with that of a traditional 0.5-hour infusion. The 3-hour infusion optimized the pharmacodynamic profile of meropenem and worked within the constraints of stability at room temperature stability. Conclusion. Prolonging the percentage of time above the minimum inhibitory concentration is a feasible option with meropenem; however, further studies are needed to quantify how this increase translates to efficacy.

BMS-284756 is a novel quinolone that lacks the six-position fluorine typical of existing compounds. Despite this structural change, BMS-284756 maintains potent antibacterial activity against gram-negative and gram-positive aerobic and anaerobic pathogens. The objective of this study was to define the pharmacodynamic profile of BMS-284756 against Streptococcus pneumoniae . Protein binding in mice was assessed by the ultrafiltration method. For pharmacodynamic studies, neutropenic ICR mice were used, as well as an immunocompetent mouse species, CBA/J, in order to evaluate the impact of white blood cells on infection outcome. Mice were infected with 10 5 to 10 6 CFU per thigh, and therapy was initiated after 2 h. Animals received BMS-284756 orally over a range of 1.25 to 100 mg/kg/day divided into one to four doses. At 0 and 24 h postinfection, thighs were harvested for bacterial density measurement. Survival was assessed during 96 h of therapy and again at 3 days after therapy. Pharmacokinetic studies were also conducted with infected mice. Protein binding was determined to be 80%. The MICs for clinical isolates ( n = 8) ranged from 0.03 to 2 μg/ml. The change in bacterial density and survival was correlated with the pharmacodynamic parameters percentage of time that the drug concentration in serum remains above the MIC, AUC (area under the concentration-time curve)/MIC ratio, and peak/MIC ratio, and the best predictor of response was the AUC/MIC ratio for both outcome measures. Total AUC/MIC ratios of 100 to 200 appear to result in maximal bactericidal effects. While a total AUC/MIC ratio exposure value of 100 (free AUC/MIC ratio, ∼20) resulted in nearly 100% survival at the conclusion of therapy, a total AUC/MIC ratio of 200 (free AUC/MIC ratio, ∼40) was required to ensure survival at 3 days posttherapy. These data demonstrate (i) the in vivo bactericidal activity of BMS-284756 against S . pneumoniae , (ii) that protein binding has a profound impact on the in vivo pharmacodynamic assessment of BMS-284756, and (iii) that an AUC/MIC ratio of 200 (free AUC/MIC ratio, ∼40) appears to best characterize the required dynamic exposure for optimization of bactericidal activity and maximal survival.

Synergy can be assessed by a variety of microbiological techniques. Mathematical modelling of synergy data can accomplish similar results and may provide more information than currently available techniques. In this study a combination of 1/4 MIC of aztreonam (AZTR) and 1 MIC of ciprofloxacin (CIPX) showed synergy against Pseudomonas aeruginosa in killing curve studies (based on the two log different criteria) at the end of 24 h. However, re-growth was always observed even when bactericidal concentrations of antibiotics were present. The surviving organisms showed a two-fold increase of MIC to CIPX after the studies and this resistance was not reversible. A mathematical model to quantitatively describe this observation is proposed.

Cethromycin (ABT-773), a new ketolide, possesses potent in vitro activity against Streptococcus pneumoniae . The objective of this study was to investigate the in vivo bactericidal activity of cethromycin against macrolide-susceptible and -resistant S. pneumoniae in a murine pneumonia model and to describe the pharmacodynamic (PD) profile of cethromycin. Eight (two macrolide susceptible, six macrolide resistant) clinical isolates of S. pneumoniae were investigated. Cyclophosphamide administration rendered ICR mice transiently neutropenic prior to intratracheal inoculation with 0.05 ml of an S. pneumoniae suspension containing 10 7 to 10 8 CFU/ml. Oral cethromycin was initiated 12 to 14 h postinoculation over a dosage range of 0.1 to 800 mg/kg of body weight/day. Lungs from seven to eight mice per treatment and control groups were collected at 0 and 24 h posttherapy to assess bacterial density. The cumulative mortality ( n = 12 to 13) was assessed at 120 h (end of therapy) and at 192 h (3 days posttherapy). Recovery of pneumococci from the lungs of infected animals prior to the initiation of therapy ranged from 4.6 to 7.2 log 10 CFU. Growth in untreated control animals over a 24-h study period increased 0.3 to 2.7 log 10 CFU. Cethromycin demonstrated a substantial bactericidal effect, regardless of macrolide susceptibility. Correlation between changes in bacterial density (24 h) and survival over both 120 and 192 h were statistically significant. All three PD parameters demonstrated a significant correlation with changes in log 10 CFU/lung (Spearman's correlation coefficient, P < 0.001); however, the goodness of fit as assessed with the maximum effect ( E max ) model revealed that the maximum concentration of free drug in serum ( C max free )/MIC and the area under the free drug concentration-time curve (AUC free )/MIC best explained the relationship between drug exposure and reductions in viable bacterial counts. These data reveal that an approximate cethromycin AUC free /MIC of 50 or C max free /MIC of 1 results in bacteriostatic effects, while higher values (twofold) maximize survival.

The objective of this study was to determine the susceptibility breakpoint of a new carbapenem, ertapenem (MK-0826), against Streptococcus pneumoniae strains based on bacterial density and survival studies in a murine thigh infection model. Sixteen S. pneumoniae isolates for which MICs ranged from 0.015 to 4.0 mg/liter were tested with neutropenic ICR mice. Animals were infected with bacteria at 10 5 to 10 6 CFU per thigh and were treated with ertapenem starting at 2 h postinfection for 4 days. Ertapenem was given subcutaneously at 50 mg/kg of body weight every 6 h, which simulates the human pharmacodynamic profile (in particular, the duration of time that the concentration of free drug remains above the MIC of 2 mg/liter). At 0 and 24 h postinfection, thighs were harvested for bacterial density determination. Survival was assessed during 4 days of therapy and 3 days after the therapy. A protein binding study was conducted with mice by use of the ultrafiltration method. Protein binding in mice was approximately 95%, which is comparable to that in humans. The average change in bacterial density ranged from −0.22 to −4.4 log CFU per thigh over 24 h compared to 0-h controls. The extent of microbial eradication was dependent on the MIC for the S. pneumoniae isolate. Substantial bactericidal activities (i.e., killing of approximately 2 log CFU per thigh) were consistently observed against isolates for which MICs were ≤2 mg/liter, which also resulted in nearly 100% survival during the 4 days of drug dosing and 3 days after the therapy. Less-pronounced and highly variable bactericidal activities were detected against isolates for which the MIC was 4 mg/liter. Substantial enhancement in bactericidal activity was observed for CBA/J mice and is attributed to the contribution of the host defenses in the immunocompetent species. Assessment of the effectiveness of ertapenem by bacterial-density reduction over 24 h and by survival over 4 days of therapy in the murine thigh infection model reveals that the drug maintains maximal efficacy against S. pneumoniae isolates for which the MIC of this agent is ≤2 mg/liter.

Standard doses of piperacillin/tazobactam (9-13.5 g over 24 h) administered by continuous infusion (CI) routinely provide serum concentrations in excess of the susceptibility breakpoint (< or =16/4 micro g/ml) for most Enterobacteriaceae. Since the breakpoint of this agent for Pseudomonas aeruginosa is considerably higher (< or=64/4 micro g/ml), the likelihood of obtaining adequate drug exposures with these doses against this bacterium is currently unknown. Monte Carlo simulation was utilized to determine the probability of obtaining adequate piperacillin concentrations above its MICs for P. aeruginosa in patients receiving CI. MICs of 557 P. aeruginosa isolates were determined by E-test and a distribution was constructed for the 496 susceptible isolates. Using a previously validated population pharmacokinetic equation, steady-state serum concentrations were estimated for 210 patients who received piperacillin/tazobactam via CI. A Monte Carlo simulation was performed to predict the probability of obtaining concentrations at the MIC, 2 x MIC, 4 x MIC, 5 x MIC, and 6 x MIC for patients infected with susceptible P. aeruginosa isolates. MICs ranged from 0.09 to 64 micro g/ml with modal and median values of 3 and 4 micro g/ml, respectively. Steady-state concentrations of 51.14 +/- 17.52 micro g/ml were estimated in our patient population. The simulation resulted in a median level of exposure 12.62 times the MIC. The level of certainty of obtaining concentrations at the MIC, 2 x MIC, 4 x MIC, 5 x MIC, and 6 x MIC for piperacillin administered by CI was 97, 93, 85, 81, and 77%, respectively. Despite concern for the place of CI piperacillin/tazobactam in the management of P. aeruginosa infections due to the higher established breakpoint, these data suggest a high probability of achieving adequate drug exposure against susceptible isolates with this dosing regimen.

Previous studies have demonstrated a significant reduction in the oral bioavailability of trovafloxacin and ciprofloxacin when administered concomitantly with an intravenous opiate, such as morphine. This decrease in absorption results in a 36% and 50% lower AUC for trovafloxacin and ciprofloxacin, respectively, which could cause clinical failures. The authors investigated the possibility of a similar interaction between oxycodone and gatifloxacin. Twelve healthy volunteers were randomized in an open-label, two-way crossover study to receive oxycodone (5 mgpo Q4H) andgatifloxacin (400 mg po 1 h) after starting the oxycodone or gatifloxacin 400 mg po alone. Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdosing. No significant difference was noted (p > 0.05) in AUC (31.6 +/- 7.3 vs. 31.7 +/- 7.1) and Cmax (3.2 +/- 0.6 vs. 3.0 +/- 0.6) for gatifloxacin versus gatifloxacin/oxycodone regimens; however, the tmax (1.8 +/- 0.8 vs. 4.3 +/- 1.5) was significantly delayed (p < 0.001). It was concluded that oral oxycodone and gatifloxacin can be administered concomitantly without a significant decrease in bioavailability.

The pharmacodynamic profile of clarithromycin (CLR) was evaluated with a murine model of pneumonia. Eight Streptococcus pneumoniae isolates, including three macrolide-sensitive and five macrolide-resistant strains, were inoculated intratracheally into immunocompromised ICR mice as 10 8 -CFU bacterial suspensions. Orally administered CLR daily doses ranging from 5 to 600 mg/kg of body weight were given over 5 days, during which animal survival was monitored. The bacterial density in lung tissues was examined after 24 h of CLR treatment and in control groups. Pharmacokinetic analysis of CLR in mice demonstrated that the regimen of 150 mg/kg twice a day was representative of human pharmacokinetics and was used to compare the efficacy of CLR against sensitive and resistant S. pneumoniae strains. Immunocompetent CBA/J mice were also infected and treated as described above and evaluated for bacterial density and survival to assess the effect of the presence of leukocytes. All three pharmacodynamic parameters, the duration (percent) of the time that serum CLR concentrations remain above the MIC (%T>MIC), the ratio of the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) to the MIC, and the ratio of the maximum concentration of drug in serum to the MIC, were found to be closely correlated to CLR bacterial efficacy ( P < 0.001). Furthermore, all parameters had close correlation to bacterial density ( r 2 = 0.72 to 0.82), median survival ( r 2 = 0.93 to 0.94), and total percent survival ( r 2 = 0.91 to 0.92). These in vivo data suggest that the bacterial activity of CLR is closely correlated with all three parameters over a wide range of exposures and, as a consequence of parameter interdependency, AUC 0-24 /MIC is the most reasonable predictor of antibiotic efficacy. In this neutropenic pneumonia model, CLR was less efficacious against S. pneumoniae strains for which MICs were ≥4 μg/ml. However, the presence of leukocytes in the immunocompetent mice resulted in improved bactericidal activity, relative to that in the neutropenic animals, despite an MIC of 4 μg/ml.

Study Objective. To compare the pharmacokinetic and pharmacodynamic profiles of two dosing regimens for piperacillin-tazobactam against commonly encountered pathogens. The regimens compared were piperacillin 4.0 g-tazobactam 0.5 g administered every 8 hours, and piperacillin 3.0 g-tazobactam 0.375 g administered every 6 hours. Design. Multiple-dose, open-label, randomized, crossover study. Setting. Clinical research center at Hartford Hospital. Subjects. Twelve healthy volunteers. Intervention. The two dosing regimens for piperacillin-tazobactam were administered intravenously in crossover design. Blood was sampled after the third dose. Measurements and Main Results. Drug concentrations were determined by a validated high-performance liquid chromatography assay. The percentage of time above minimum inhibitory concentration (%T>MIC) for piperacillin was calculated for a range of MIC values. The maximum concentration (Cmax), area under the concentration-time curve (AUC0-τ), and total clearance of piperacillin differed significantly between the two study regimens, as did the Cmax, AUC0-τ, volume of distribution, and total clearance of tazobactam (p MIC for MIC values 8–16 μg/ml; a similar value for the piperacillin 3.0 g-tazobactam 0.375 g regimen was 16–32 μg/ml. Conclusion. Although statistically significant differences in the pharmaco-dynamic profile were noted for the regimens, both provide adequate T>MIC against commonly encountered pathogens considered susceptible to piperacillin-tazobactam. However, for treatment of Pseudomonas aeruginosa infection, combination therapy or higher-dosage regimens (e.g., piperacillin 3.0 g-tazobactam 0.375 g every 4 hours, piperacillin 4.0 g-tazobactam 0.5 g every 6 hours, or continuous-infusion piperacillin 12 g-tazobactam 1.5 g/day) may be a prudent option when full MIC data are unavailable.

STUDY OBJECTIVE: To compare continuous versus intermittent administration of piperacillin-tazobactam with regard to clinical, microbiologic, and economic outcomes. DESIGN: Prospective, open-label controlled study SETTING: Community teaching hospital. PATIENTS: Ninety-eight hospitalized patients prescribed piperacillin-tazobactam. INTERVENTION: Substitutions were implemented so that 47 patients initially prescribed intermittent infusion of piperacillin-tazobactam were switched to continuous infusion of this drug combination. Dosages varied in accordance with the type of infection and each patient's renal function. Fifty-one other patients with similar demographics and types of infection received intermittent infusion with piperacillin-tazobactam. MEASUREMENTS AND MAIN RESULTS: Clinical success rates were 94% for the continuous-infusion group and 82% for the intermittent-infusion group (p=0.081). Microbiologic success rates were 89% for the continuous-infusion group and 73% for the intermittent-infusion group (p=0.092). Days to normalization of fever were significantly lower (p=0.012) in the continuous-infusion group (1.2 +/- 0.8 days) than in the intermittent-infusion group (2.4 +/- 1.5 days). Level 1 and level 2 costs/patient were both reduced by continuous infusion, although the difference was statistically significant only for level 2 costs ($399.38 +/- 407.22 for continuous infusion vs $523.49 +/- 526.85 for intermittent infusion, p=0.028). CONCLUSION: 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.

Extended-interval aminoglycoside dosing (EIAD), while a relatively recent concept in mainstream clinical practice, actually has its roots in the mid 1970s. Early trial and error approaches of manipulating the dosage regimen to avoid toxicity and improve efficacy have helped to characterize the pharmacodynamic properties of these drugs. The increasing successful use of EIAD and improved understanding of pharmacodynamics has helped this dosing regimen gain acceptance into routine clinical practice. A 1998 United States survey demonstrated that approximately 75% of hospitals have adopted EIAD into routine patient care. However, controversy still exists regarding some aspects of infrequent aminoglycoside administration, such as length of the drug-free interval and patient exclusion criteria. After more than 50 years of experience with the aminoglycosides we continue to learn how to most appropriately use these drugs.

When piperacillin/tazobactam has been used to treat hospitalized patients with serious infections, including nosocomial pneumonia caused by Pseudomonas aeruginosa, it has usually been dosed at 3.375 g q4h to provide serum concentrations above commonly encountered organisms’ MICs (T > MIC) for at least 40–50% of the dosing interval. Pharmacodynamic principles suggest that a similar efficacy can be realized with extended dosing intervals when a larger dose (e.g. 4.5 g q6h) is administered, which was the objective of this study. Twelve healthy volunteers, 29.4 ± 8.9 years of age, were enrolled in this multiple-dose, open-labeled, randomized, two-period crossover study. Blood samples were collected after the third dose and concentrations of piperacillin/tazobactam were determined with a validated HPLC method. Pharmacokinetic profiles were determined by noncompartment analysis. T > MIC of piperacillin was calculated for a range of MIC values. Piperacillin/tazobactam was well tolerated in 11 subjects who completed both regimens. The Cmax, T1/2, K, and AUC of P were significantly different according to a paired t test (p < 0.05) between two study regimens. Significant differences (p < 0.05) in tazobactam regimens were noted for Cmax, and AUC. The piperacillin/tazobactam regimen of 4.5 g q6h achieved a 44% T > MIC for MIC values of ≤16 µg/ml, while the 3.375-gram q4h regimen achieved 42% T > MIC, for MIC values of ≤32 µg/ml. Dosage regimens for treating serious infections can be extended safely and effectively to 4.5 g q6h and obtain at least 40–50% T > MIC in the coverage of pathogens implicated with serious infections, including P. aeruginosa.

ABT-773 is an investigational ketolide antimicrobial agent with an in-vitro bactericidal activity against macrolide-susceptible and -resistant Streptococcus pneumoniae. The pharmacokinetics of this drug candidate were evaluated in lung-infected (108 CFU mL−1 starting inoculum) mice following a single dose (25, 50, 100 or 200 mg kg−1) oral administration as a solution in 10 % of 95% ethanol and 90% of 0.1 M pH 6.5 phosphate buffer solution. Serum ABT-773 concentrations were measured using a validated HPLC assay with fluorescence detection (excitation at 324 nm and emission at 364 nm). Population pharmacokinetic analysis was performed using the NONMEM computer program. Results from data analysis showed non-linear pharmacokinetics of ABT-773, noted by the increases in half-life (3.1 to 27.2 h) and AUC/dose (23.7 to 149 mg h−1 L−1 mg−1), with doses from 25 to 200 mg kg−1. A non-linear one-compartment model with parallel capacity-limited and linear first-order elimination best described the pharmacokinetics of ABT-773 in the mouse. The total volume of distribution was 0.316 L. The clearance for the linear first-order elimination was 0.0027 L h−1. The Vm and Km were 0.0385 L h−1 and 0.141 mg L−1, respectively, for the capacity-limited elimination.

The pharmacodynamic profile of modithromycin (EDP-420, EP-013420, S-013420), a novel bicyclolide, was evaluated in a neutropenic pneumococcal murine pneumonia model. Streptococcus pneumoniae median minimum inhibitory concentrations (MICs) for five genotypically diverse isolates ranged from 0.016 μg/mL to 0.125 μg/mL and were unaffected by macrolide or penicillin resistance determinants. The modithromycin dosing regimens (total daily doses of 3.125-1000 mg/kg/day) were derived from the pharmacokinetic profile of the compound in infected mice and were selected to produce a wide range of exposures. Dose-response relationships characterised using the Emax model demonstrated high correlations both with the ratio of the area under the concentration-time curve to MIC (AUC/MIC) and the ratio of the maximum drug concentration to MIC (Cmax/MIC). However, dose fractionation studies suggest that the AUC/MIC is the predominant driver of in vivo efficacy. The free drug AUC/MIC (fAUC/MIC) required for stasis and for 80% of maximum activity ranged from 4 to 53 and 25-99, respectively. The fAUC/MIC needed to achieve a 1 log reduction in bacterial density, which is a conventional measure of the required exposure in man to reliably predict efficacy, ranged from 9 to 69. These data demonstrate the in vitro and in vivo potency of modithromycin against S. pneumoniae irrespective of its phenotypic profile to the macrolides or penicillin.

A multiple-dose, open-labelled, randomized, two period crossover human volunteer study was performed (i) to describe the pharmacokinetic profile and safety profile of piperacillin and tazobactam (P/T) administered 6.0/0.75 g and 8.0/1.0 g q12h and (ii) to characterize the pharmacodynamic profile of these regimens against a variety of common targeted pathogens. Blood samples were collected after the third dose and concentrations of P/T were determined by a validated high-performance liquid chromatography assay. Pharmacokinetic profiles of P/T were determined by non-compartment analysis. Percentage time above the MIC (%TMIC) of piperacillin was calculated for a range of MICs. In this study, no adverse events were attributed after multiple administrations of either 6.0/0.75 g or 8.0/1.0 g dose regimens. The peak concentration, half-life and area under the curve (AUC0-(0-tau)) of piperacillin were significantly different by a paired t-test (P0.05) between the two study regimens. The trough concentration, half-life and area under the curve (AUC0-(0-tau)) of tazobactam were substantially different from parameters reported previously for conventional regimens. The 8.0/1.0 g regimen provided 50% TMIC for MICsor =32 mg/L, while a similar value for the 6.0/0.75 g regimen wasor = 16 mg/L. High-dose P/T regimens with extended interval were well tolerated and provide adequate dynamic exposure for a variety of susceptible pathogens.

The pharmacodynamic parameters of peak serum drug concentration/MIC (peak/MIC) ratio and the area under the curve (AUC)/MIC ratio have been used to characterize in vivo drug exposure and its relationship to bacterial killing for the fluoroquinolones. Our study objectives were to describe the pharmacodynamic relationship between gatifloxacin exposure and outcome as assessed by bacterial density and survival in an immunocompromised murine thigh model of pneumococcal infection and to assess the relationship between drug exposure and these outcomes in an immunocompetent host. ICR mice were rendered neutropenic, and thigh infection was induced by intramuscular administration of 0.1 ml of 10 5 to 10 7 CFU of Streptococcus pneumoniae /ml. Mice received 1 to 5 mg of uranyl nitrate/kg of body weight at day −3 and were randomized to receive 10 to 80 mg of gatifloxacin/kg every 6 to 24 h orally, starting at 2 h postinoculation. Bacterial density studies were completed 24 h after initiation of therapy, and survival was assessed after 4 days of treatment. MICs for clinical isolates ( n = 8) ranged from 0.25 to 1.0 μg/ml. Correlations were assessed between the change in bacterial density, as well as survival, and the AUC/MIC ratio, peak/MIC ratio, and the duration of time that serum drug concentration remained above the MIC. The best predictor of bacterial response was the AUC/MIC ratio for both outcome measures. There was greater efficacy, as measured by a decrease in log change in CFU as well as by survival data, in the immunocompetent mice compared to the immunocompromised mice. These data demonstrate (i) the appropriateness of the AUC/MIC ratio as a dynamic predictor of response to pneumococcal infection for the fluoroquinolones, (ii) that gatifloxacin AUC/MIC ratios of 30 to 40 appear to optimize bactericidal activity and survival in this model, and (iii) that immunocompetency of the host plays a role in efficacy.

A prospective, randomized pilot study was undertaken to compare the efficacy of continuous versus intermittent ceftazidime in ICU patients with nosocomial pneumonia. Ceftazidime was administered either as a 3 g/day continuous infusion (CI) or an intermittent infusion (II) of 2 g every 8 h. In addition, all patients received concomitant once-daily tobramycin. The demographics of the evaluable patients (n = 35) were similar between the groups: age (years), CI 46 +/- 16, II 56 +/- 20; Apache score, CI 14 +/- 4, II 16 +/- 6; time (days) from admission to diagnosis, CI 9 +/- 6, II 9 +/- 6. Clinical efficacy, defined as cure/improvement was similar between groups [n (%), CI 16/17 (94), II 15/18 (83)], while microbiological response was also comparable [n (%), CI 10/13 (76), II 12/15 (80)]. Minimal inhibitory concentrations (MICs) for all isolates were measured throughout the treatment course; there was no development of resistance during therapy for either regimen. While limited clinical data exist, our results suggest that the use of ceftazidime by CI administration maintains clinical efficacy, optimizes the pharmacodynamic profile and uses less antibiotic compared with the standard 2 g every 8 h intermittent dosing regimen.

Study Objective. To determine if continuous-infusion ceftazidime is more cost-effective and efficacious than intermittent infusion in patients with nosocomial pneumonia. Design. Prospective, open-label, randomized trial. Setting. Large, community teaching hospital. Patients. Intensive care unit (ICU) patients with nosocomial pneumonia. Interventions. Ceftazidime 3 g/day was administered as a continuous infusion or as 2 g 3 times/day by intermittent infusion to treat nosocomial pneumonia in the ICU. Patients also received tobramycin 7 mg/kg once/day. Measurements and Main Results. Thirty-five patients were evaluable; 17 received continuous infusion and 18 intermittent infusion. Clinical efficacy (94% and 83% successful outcomes with continuous and intermittent infusion, respectively), adverse events, and length of stay did not vary significantly between groups. Costs associated with continuous infusion, $627 ± 388, were significantly lower (p≤0.001) than with intermittent infusion, $1007 ± 430. Conclusions. Continuous infusion of ceftazidime is a cost-effective alternative to intermittent infusion for nosocomial pneumonia in the ICU.

Study Objective. To examine whether the antienterococcal efficacy of a regimen of gentamicin plus vancomycin combined with granulocyte colony-stimulating factor (G-CSF) is enhanced by concurrent therapy with interferon-γ (IFN-γ). Setting. Hospital laboratory. Intervention. Mice rendered neutropenic by cyclophosphamide were intraperitoneally inoculated with a gentamicin- and vancomycin-resistant Enterococcus faecalis isolate. Measurements and Main Results. Infected animals were randomized into treatment groups that received G-CSF alone or in combination with various dosages of IFN-γ. Additional groups of animals received vancomycin; G-CSF, G-CSF plus vancomycin, IFN-γ, and G-CSF; or vancomycin with both cytokines. Addition of IFN-γ to G-CSF regimen resulted in no significant change (p>0.05) in survival, compared with treatment with G-CSF alone. Also, the antienterococcal efficacy of antibiotic plus G-CSF was not modified by coadministration of IFN-γ. Conclusion. This study suggests that adjunctive application of combined cytokines may not be more beneficial than only G-CSF in combination with an antibiotic to treat multidrug-resistant enterococcal infection.

Previous studies have demonstrated a significant reduction in the oral bioavailability of trovafloxacin and ciprofloxacin when administered concomitantly with an intravenous opiate such as morphine. This decrease in absorption results in a 36% and 50% lower AUC for trovafloxacin and ciprofloxacin, respectively, which could cause clinical failures. The authors investigated the possibility of a similar interaction between oxycodone and levofloxacin. Eight healthy volunteers were randomized in an open-label, two-way crossover study to receive oxycodone, 5 mg p.o. Q4H, and levofloxacin, 500 mg p.o. 1 hour after starting the oxycodone or levofloxacin 500 mg p.o. alone. Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours for Cmax, tmax, and AUC determinations. There was not a significant difference (p > 0.05) in AUC (48.59 +/- 8.52 vs. 49.9 +/- 9.93), Cmax (7.73 +/- 2.6 vs. 6.6 +/- 2.0), and tmax (1.1 +/- 0.6 vs. 1.6 +/- 1.1) for levofloxacin versus levofloxacin/oxycodone regimens. It was concluded that oral oxycodone and levofloxacin can be administered concomitantly without a significant decrease in AUC, Cmax, or tmax.

Although the overall incidence of infective endocarditis in the paediatric population is considered to be low, over the last 20 years a rising trend in infective endocarditis has been observed among children. This could be due to several reasons including the availability of improved diagnostic techniques, use of continuous central venous catheters and cardiac implants increasing the risk of infection, and the survival of a greater number of infants with congenital heart disease as a result of improved medical management. The predominant causative organisms of paediatric endocarditis include staphylococci and streptococci. There is increased concern surrounding the emergence of endocarditis in children caused by methicillin-resistant Staphylococcus aureus and drug resistant strains of Streptococcus pneumoniae. The treatment approach to paediatric endocarditis is similar to that for adult patients with endocarditis because of similarities in disease pathogenesis and aetiology. The therapeutic goal is to achieve sterilisation of the cardiac vegetations. The choice of antibacterial is dependent upon the susceptibility profile of the causative organism. Vancomycin or gentamicin is recommended for enterococcal endocarditis, according to guidelines from the American Heart Association. For staphylococcal endocarditis in patients with no prosthetic valve, oxacillin or nafcillin with or without gentamicin is the treatment of choice. In the case of endocarditis caused by methicillin-resistant S. aureus, vancomycin is commonly used in patients with no prosthetic valve and a combination of vancomycin, gentamicin and rifampicin (rifampin) for patients with prosthetic material. Cefazolin or ceftriaxone is the treatment of choice for penicillin allergic paediatric patients with endocarditis caused by viridans streptococci. While there have been no major changes in endocarditis therapy for the last decade, the current focus is on the recognition of multiple-drug resistant pathogens and the use of newer agents such as quinupristin/dalfopristin in the treatment of resistant bacterial endocarditis. Prophylactic antibacterial therapy is recommended for procedures thought to be associated with the occurrence of bacteraemia involving organisms commonly associated with endocarditis. These include dental extractions and oral, respiratory tract, genitourinary, gastrointestinal or oesophageal procedures. Prophylactic antibacterials recommended by the American Heart Association during genitourinary and gastrointestinal surgical procedures in high risk patients include ampicillin + gentamicin or vancomycin + gentamicin in high risk patients with penicillin allergy. Ampicillin has been recommended for prophylaxis of bacterial endocarditis in children undergoing oral, respiratory tract or oesophageal procedures. In the case of penicillin allergy in these patients, cephalosporins, clindamycin, azithromycin or clarithromycin have been recommended. The general consensus is that antibacterial prophylaxis during dental procedure is unnecessary, and in fact propagates bacterial resistance.

Azithromycin, has been proved to be effective in the treatment and prophylaxis of a wide variety of infections. While the penetration of azithromycin into a number of types of mammalian cells has been well characterized, the influence of HIV infection on the intracellular disposition of this agent has not been studied. We therefore studied the disposition of azithromycin in polymorphonuclear (PMN) and mononuclear (MONO) leukocytes from six healthy volunteers and six volunteers with AIDS. After oral administration of a single 1200-mg dose of azithromycin (two 600-mg tablets), blood samples were collected over 6 days and intracellular azithromycin concentrations in MONOs and PMNs were measured. Analysis of the intracellular pharmacokinetics revealed an apparent difference in the MONO and PMN profile; this profile was similar for both groups. Intracellular concentrations of azithromycin remained high throughout the study period. Furthermore, no statistically significant differences in the intracellular area under the curve (11 309±2543 vs. 16 650±6254 for PMN; 14 180±3802 vs. 21 211±10 001 for MONO) were observed between the healthy and AIDS populations, respectively. Our data confirm the extensive uptake of azithromycin by white blood cells both in healthy volunteers and in AIDS patients.

This study examines those market factors that were most influential regarding decision making made by Medicare recipients in choosing a particular health insurance plan. Since Medicare recipients can now choose health care insurance providers, companies are actively competing for this possibly very lucrative market share. A cross sectional cohort research design using a sample of 135 subjects was surveyed. Two separate groups of contributing factors to an individual's selection of a plan were measured. Factors such as level of understanding, level of perceived health, and satisfaction with the plan in terms of hospital choice were most important. Surprisingly, preference of marketing media did not provide any significant results.

Objective: This study evaluated the quality of 40 generic clarithromycin products from Latin America and Asia. Materials and Methodsv: The generic products were examined visually, assayed by high pressure liquid chromatography for clarithromycin content and impurities, tested for dissolution properties, and compared with the innovator product manufactured by Abbott Laboratories. Results: This survey found that many generic clarithromycin products are not equivalent to the innovator product, falling short of the approved, registered specifications for the innovator product. Overall, 20% (8 of 40) of all generic tablets tested, and 33% (6 of 18) of tablets from Latin America, failed to contain between 95 and 105% of the clarithromycin claimed in the label, thus falling short of the approved registered specification for the innovator product. A total of 70% (28 of 40) of products tested released less drug in 30 minutes than did the innovator tablets, although they still met the dissolution specification requiring that 80% of the drug must dissolve in 30 minutes; one generic product failed to meet the specification. A total of 60% (24 of 40) of the generic products tested exceeded the Abbott Laboratories’ 3% limit for total impurities in bulk drug, and 70% (28 of 40) exceeded the Abbott Laboratories’ 0.8% limit for 6,11 di-O-methyl erythromycin A. Conclusions: These results suggest that generic tablets are not equivalent to the innovator product, raising concerns that clinical trial results achieved with branded clarithromycin (Abbott Laboratories) should not be extrapolated to generic products.

Moxifloxacin (BAY 12-8039) is a new 8-methoxy-fluoroquinolone antibacterial agent. The minimum inhibitory concentration for 90% of organisms (MIC 90 ) is less than 0.25 mg/L for commonly isolated community-acquired respiratory tract pathogens including penicillin-susceptible and -resistant Streptococcus pneumoniae, Haemophilus sp, and Moraxella catarrhalis, and less than 1.0 mg/L for atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. To date, emergence of resistance to moxifloxacin has been uncommon, including selection of resistance under experimental conditions (methicillin-sensitive Staphylococcus aureus, S. pneumoniae). A postantibiotic effect is observed for both gram-positive and gram-negative bacteria. Human pharmacokinetics in healthy volunteers after a single 400-mg oral dose were mean maximum concentration (C max ) 3.2 mg/L, area under the curve (AUC) 37 mg.hour/L, and terminal elimination half-life 12.0 hours. At steady-state, C max and AUC were approximately 4.5 mg/L and 48 mg.hour/L, respectively. Because of a balanced system of excretion, no dosage adjustments are required in patients with renal or hepatic impairment. Moxifloxacin also has excellent penetration into upper and lower respiratory tissues. Laboratory pharmacodynamic models suggest that MIC and AUC values predict therapeutic response. Notably, the drug can be administered once/day and is not associated with drug interactions secondary to altered hepatic metabolism. In addition, since its metabolism does not involve the cytochrome P450 system, many common drug interactions are absent. The agent is being investigated in clinical trials and shows promise as a safe and effective once-daily treatment of respiratory infections. In addition, its chemical structure and pharmacokinetic and pharmacodynamic properties indicate that it has enhanced potential to minimize emergence of bacterial resistance, which should make it an excellent choice for treating respiratory tract infections now and in the future.

Principles of antibiotic pharmacodynamics include factors that are important for effective eradication of bacteria as well as the suppression of resistance. For effective eradication of bacteria and a good clinical outcome, a ratio for the area under the plasma concentration-time curve relative to the minimum inhibitory concentration (AUC/MIC) of greater than 100 is needed for gram-negative organisms, and a level of greater than 30 is required for gram-positive organisms. Pharmacodynamic principles can also be used to devise the optimal administration regimen for specific antimicrobial agents. Pharmacodynamic analysis of the activity of levofloxacin against Streptococcus pneumoniae revealed that, 99% of the time, actual hospitalized patients achieve an AUC/MIC of greater than 30. This indicates that levofloxacin will be very effective in treating S. pneumoniae infections in the majority of patients. Cost of treatment is an increasing concern voiced by healthcare providers and users alike. This has led to a much greater emphasis placed upon the cost of individual drugs used in the management of infections. However, when evaluating the cost of an antibiotic, it is extremely important that not only are the direct acquisition costs assessed, but consideration also given to other aspects incurring a financial burden, such as drug preparation cost, supplies, costs of treating adverse events or any treatment failures. It is only by having such a full assessment of costs that realistic financial comparisons can be made between different antibiotics.