[Show abstract][Hide abstract] ABSTRACT: In addition to bactericidal activity, macrolide antibacterials possess clinically relevant properties such as immunomodulatory activity. Whether such activity extends to novel antibacterials that are structurally related to macrolides, such as the ketolides, remains largely unknown. The objective of this study was to evaluate the in vivo immunomodulatory profile of the first ketolide antibacterial - telithromycin in a murine neutropenic thigh infection model. Specific pathogen-free, female ICR mice were rendered transiently neutropenic with intraperitoneal cyclophosphamide. Thighs were inoculated with 10(6) colony-forming units of a single clinical isolate of Streptococcus pneumoniae. Once inoculated, mice (n=500) received single oral doses of telithromycin (10, 25 or 50 mg/kg of body weight) or no treatment (control). Blood was obtained via cardiac puncture prior to and at 2, 4, 8, and 24 h after dose administration for determination of cytokine concentrations. Significant post-inoculation elevations of interleukin (IL)-1beta, IL-6, and IL-10 were noted in untreated controls over 24 h. Telithromycin attenuated these increases and the suppression of both IL-6 and IL-10 release was observed to be dose dependent. Systemic concentrations of IL-2 and tumor necrosis factor alpha showed an upward trend over the initial 8-h post-inoculation period in the telithromycin group. These data therefore reveal novel in vivo immunomodulatory effects of telithromycin. Further studies are warranted to determine whether such effects contribute to the therapeutic efficacy of the drug in patients with acute respiratory tract infections.
[Show abstract][Hide abstract] ABSTRACT: Antimicrobial efficacy is dependent on the ability of the agent to reach the site of infection. To assess the bronchopulmonary drug disposition of a novel ketolide, telithromycin (TEL), the epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations were utilized as a surrogate marker for lung penetration.
Adult subjects scheduled for diagnostic bronchoscopy received oral TEL 800 mg once daily for 5 days. Plasma and bronchoalveolar lavage (BAL) samples were collected 2, 8, 12, or 24 h after the last TEL dose. TEL concentrations in the ELF and AM were determined using a validated HPLC assay. ELF drug concentrations were calculated using the urea dilution method.
Seventeen subjects with a mean age 65 +/- 13 years and a mean weight of 81 +/- 25 kg completed this open-label study. The median (range) TEL concentrations in plasma and ELF, respectively, were 1.09 mg/l (1.00-4.81) and 3.91 mg/l (2.64-9.59) at 2 h (n = 6), 0.48 and 1.09 mg/l at 8 h (n = 1), 0.65 mg/l (0.18-1.55) and 1.81 mg/l (0.61-10.0) at 12 h (n = 5), and 0.11 mg/l (0.09-0.24) and 0.69 mg/l (0.15-1.58) at 24 h (n = 5). The median AM concentrations obtained from these subjects were 53.35 mg/l at 2 h, 32.55 mg/l at 8 h, 65.96 mg/l at 12 h, and 26.43 mg/l at 24 h. Overall TEL was well tolerated. No discontinuation was required due to an adverse event.
TEL displayed high intrapulmonary penetration with ELF concentrations exceeding that of plasma at all time points. AM intracellular concentrations were multiple times higher than in the ELF and plasma. These data support the clinical efficacy of TEL against intracellular and extracellular pathogens, particularly with Streptococcus pneumoniae having an MIC(90 )well below achievable concentrations at the site of infection.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Feb 2005 · Clinical Drug Investigation
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To develop a HPLC method for the determination of moxifloxacin in special growth media. METHODS: With gatifloxacin as the internal standard, the protein in 100 μL of samples containing broth media was precipitated by acetonitrile. The supernatant layer was evaporated under nitrogen stream and the residual was reconstituted with 200 μL of 0.01 mol·L-1 HCl. A Alltech Nucleosil 100(C18) column was used and the mobile phase consisted of buffer-methanol-acetonitrile (66.8:15.1:18.1), the buffer consisted of triethylamine-phosphoric acid-water (0.37:0.30:99.3). The flow rate of mobile phase was 1.3 mL·min-1. Excitation and emission wavelengths of the fluorometer were at 295 and 418 nm, respectively. RESULTS: A linearity was obtained from 1.0 to 50.0 μg·mL-1 of moxifloxacin in broth (5% LHB-CAMHB, a cation-adjusted mueller-hinton broth with 5% lysed horse blood) with a good correlation coefficient (r = 0.999 9, n = 7). The intra-run and inter-run validation were less than 0.89%. The mean recoveries were 98.43% and 103.51% for the high and low concentrations of the quality control samples, respectively. CONCLUSION: The HPLC assay was sensitive, reliable, reproducible and simple, and the run time was only 10 minutes. The method was successfully applied to unknown samples of moxifloxacin in 5% LHB-CAMHB obtained from an in vitro model BAL study.
No preview · Article · Sep 2004 · Journal of Chinese Pharmaceutical Sciences
[Show abstract][Hide abstract] ABSTRACT: Daptomycin has demonstrated in vitro activity against gram-positive organisms, including Streptococcus pneumoniae. However, the pharmacodynamic (PD) profile of daptomycin is needed to relate the activity of the drug to biologically achievable concentrations.
The PD profile of daptomycin against four S. pneumoniae isolates was determined using the immunocompromised murine thigh model. Due to the high protein binding of this agent, PD parameters were calculated based on free drug exposures. Efficacy was assessed by the change in log colony-forming units (CFU) in thighs after 24 h of drug treatment.
Daptomycin produced a 7.1 (95% confidence interval 7.0-7.2) log(10) CFU kill. The ratio between overall drug exposure and the minimum inhibitory concentration (MIC) (AUC/MIC) was the most predictive of the PD parameters. The S. pneumoniae AUC/MIC required for static effects was 12 (95% confidence interval 10-14). Eighty percent and 99% of maximal kill was achieved at ratios of 35 (95% confidence interval 32-39) and 184 (95% confidence interval 160-208), respectively.
Clinically achievable serum drug exposures produced by the lowest dose of daptomycin currently studied in humans (4 mg/kg/day) should result in a potent in vivo bactericidal effect against infections due to S. pneumoniae such as bacteremia, where serum drug concentrations adequately reflect the concentration at the site of infection.
[Show abstract][Hide abstract] ABSTRACT: Itraconazole is often given for fungal prophylaxis to renal transplant recipients, who require concomitant cyclosporine in the immediate posttransplant period. We determined the extent of the pharmacokinetic interaction between cyclosporine and itraconazole oral solution in renal transplant recipients and the effect on daily drug costs.
This was a single-center, open-label, nonrandomized study. Posttransplantation, renal transplant recipients received itraconazole solution 200 mg twice daily and cyclosporine, dosed to achieve target concentrations. Once at steady state, blood samples were collected over 12 hours for pharmacokinetic evaluation of cyclosporine, itraconazole, and hydroxy-itraconazole. Itraconazole was discontinued after approximately a 3-month prophylaxis regimen. Cyclosporine doses were titrated to achieve target concentrations and cyclosporine concentrations were once again determined when steady state was achieved. A noncompartmental analysis was used to analyze cyclosporine pharmacokinetic parameters. The pharmacoeconomic impact was measured based on the percent change in dose of cyclosporine when administered with and without itraconazole. Drug costs were calculated using the average wholesale price. The cost per patient, as well as the average cost, was calculated for the cyclosporine/itraconazole combination, as well as the cyclosporine regimen alone.
Eight renal transplant recipients completed the study. All were included for itraconazole analyses and seven for cyclosporine analyses. Mean peak and trough itraconazole levels were 1.64 +/- 0.82 and 1.23 +/- 0.90 microg/mL respectively. Mean peak and trough hydroxy-itraconazole levels were 2.37 +/- 1.55 and 2.20 +/- 1.48 microg/mL, respectively. While on itraconazole, a 48% reduction in the mean total daily dose of cyclosporine was necessary to maintain target concentrations (171 +/- 63.6 versus 329 +/- 103.5 mg, P =.003). This reduction in cyclosporine dose resulted in a discounted itraconazole daily drug cost of approximately 29.5%.
Administering itraconazole with cyclosporine allows for a decrease in the cyclosporine dose, thus lowering daily drug costs and providing adequate antifungal coverage with itraconazole and hydroxy-itraconazole trough concentrations above the MIC(90) of Candida and Aspergillus spp.
No preview · Article · Jan 2004 · Transplantation Proceedings
[Show abstract][Hide abstract] ABSTRACT: To describe the pharmacodynamic profile of daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) and Enterococci species based on bacterial density in an immunocompromised mouse thigh infection model.
The pharmacodynamic (PD) profile of daptomycin was determined against two MRSA, one vancomycin-resistant Enterococcus faecium, and one vancomycin-susceptible Enterococcus faecalis using the immunocompromised murine thigh model. Efficacy was assessed by the change in log10 cfu in thighs after 24 h of drug treatment.
Daptomycin produced a maximal kill of 4.5-5 log10 cfu against the MRSA and 1.5-2 log10 for the Enterococcus species. AUC/MIC was the most predictive of the PD parameters. Utilizing MICs determined in serum or broth in the calculation of the PD parameters had minimal effect on this correlation. AUCfree/MICbroth required for static effects with MRSA and Enterococcus species were 12-36 and 5-13, whereas 99% of maximal kill was achieved at ratios of 171-442 and 38-157, respectively.
These data reveal the potent in vivo bactericidal activity of daptomycin against MRSA and Enterococcus species using clinically achievable drug exposures (dose 4-6 mg/kg per day) currently under investigation in man.
Full-text · Article · Oct 2003 · Journal of Antimicrobial Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Quinupristin-dalfopristin (Q/D) is often utilized in critically ill patients, some of whom require CVVH. This study was undertaken to determine the clearance of O/D and their main active metabolites (RPR 100391, RP 69012, RP 12536) via CVVH in the swine model.
Q/D 7.5 mg/kg was intravenously administered over 0.5 h to 12 swine after induction of acute renal failure by ligation of the renal arteries. At 0.5 h post injection, the CVVH procedure was initiated and continued for 8 hours at the following pump rates: (1)100 mL/min, (2)180 rnL/min, and (3)100 mL/min with dialysis (flow rate: 1 L/h). Blood and ultrafiltrate samples were collected at 1 h intervals and assessed by a validated HPLC method.
Plasma analysis suggests rapid metabolism to the main active metabolites which are appreciably cleared as demonstrated by high clearance and sieving coefficient estimates. Mean clearance estimates for RP 69012, RP 100391, and RP 12536 are 729, 777, and 578 mL/h in the 100 mL/min CVVH group, 772, 785, 685 mL/min in the 180 mL/min CVVH group, and 753, 791, 616 mL/min in the 100 mL/min CVVH group with 1 L/h dialysis, respectively.
These data reveal that Q/D is rapidly metabolized and the metabolites are cleared to a large extent via CVVH. Due to the considerable contribution of the metabolites to overall in vivo activities, additional studies are required to fully quantify their removal before final dosage modifications for patients undergoing CVVH can be recommended.
No preview · Article · Feb 2002 · The International journal of artificial organs
[Show abstract][Hide abstract] ABSTRACT: 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 (%T > MIC) 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 (P < 0.05) 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% T > MIC for MICs < or =32 mg/L, while a similar value for the 6.0/0.75 g regimen was < or = 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.
No preview · Article · Sep 2001 · Journal of Antimicrobial Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: The study was undertaken to evaluate the single-dose absorption, elimination, and systemic bioavailability of enterally administered fluconazole relative to intravenous fluconazole in ICU patients. Fluconazole pharmacokinetics were evaluated in five patients who had normal gastrointestinal motility, normal renal and hepatic function. A single 200 mg dose of fluconazole was administered either as an intravenous infusion over 1 h or the suspension given via a feeding tube in a crossover design. Fluconazole serum concentrations were determined by a validated HPLC method and the pharmacokinetic parameters of fluconazole were calculated using non-compartmental analysis. The absolute bioavailability of the suspension as determined by a ratio AUC susp/AUC IV was 77.4±44%.
No preview · Article · Jan 2001 · Journal of Infectious Disease Pharmacotherapy
[Show abstract][Hide abstract] ABSTRACT: It has been demonstrated previously that, in non-neutropenic animals, interferon-gamma markedly enhances the efficacies of gentamicin and vancomycin against Enterococcus faecalis resistant to these antibiotics. The aim of our study was to determining whether granulocyte colony-stimulating factor (G-CSF) can be beneficial as an adjunct to gentamicin and vancomycin in the treatment of the same infection in neutropenic mice. After induction of neutropenia by cyclophosphamide, mice were inoculated ip with the organism. The infected animals received sc administrations of G-CSF, antibiotic or a combination of both agents at determined dosing regimens. Infected animals treated with G-CSF alone showed a dose-dependent increase in survival. The inoculum size used in establishing infection affected the effectiveness of the cytokine. Survival was significantly (P: < 0.01) better in the infected animals given gentamicin and vancomycin plus G-CSF than in those given antibiotics or G-CSF alone. The possibility of pharmacokinetic interaction between G-CSF and each of the antibiotics was examined. The cytokine significantly increased the plasma clearance of gentamicin, with a resultant decrease in the area under the concentration-time curve (AUC), while the disposition of vancomycin was not affected. This study suggests that G-CSF may be a useful adjunct to gentamicin and vancomycin for the treatment of multidrug-resistant E. faecalis infection in neutropenic patients.
[Show abstract][Hide abstract] ABSTRACT: This study evaluated the quality of 11 generic clarithromycin products obtained in Poland, Slovakia, Slovenia, or Israel and manufactured in Slovenia or Israel. 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. Fifty-five percent of generic products fell short of the specifications for the innovator product. Ten percent of the generic products did not contain the amount of clarithromycin claimed in the label; 18% released less drug than did the branded tablets in the standard dissolution assay. In light of these results, it is not possible to conclude that all generic tablets are of the same quality as the innovator product; clinical trial results achieved with branded clarithromycin should not be extrapolated to generic products.
No preview · Article · May 2000 · Advances in Therapy
[Show abstract][Hide abstract] ABSTRACT: Recent in vitro and in vivo data have substantiated the beneficial effects of macrolides/ azalides for use against Pseudomonas aeruginosa. While macrolides/azalides are not very potent in vitro antimicrobial agents against this pathogen, they appear to have an adjunctive role by either altering the course of infection owing to their inhibition of biofilm production or modulation of the host anti-inflammatory response, or both. To determine the in vitro and in vivo effects of clarithromycin as adjunctive therapy with ceftazidime against a mucoidproducing strain of P. aeruginosa, we performed a standard time-kill experiment and a pneumonia model in mice, respectively. Time-kill studies were performed over a 24 h period with varying concentrations of clarithromycin and ceftazidime alone or in combination. Synergic activity was noted with the use of 0.5 x MIC of ceftazidime combined with either 0.5 or 2 x MIC of clarithromycin. Neutropenic mice were infected with 10(8) cfu of mucoid P. aeruginosa intranasally to produce pneumonia and subsequently treated with oral clarithromycin (100 mg/kg) and/or sc ceftazidime (1500 mg/kg) as monotherapy or in combination. The addition of 5 days of clarithromycin to the ceftazidime regimen significantly improved survival as compared with the beta-lactam alone (48% versus 32%, P = 0.04). While a statistically significant difference was not detected with the addition of 3 days of clarithromycin therapy, a trend towards improved survival was noted with this regimen (38% versus 32%). These data demonstrate the adjunctive potential of clarithromycin when administered in combination with an antipseudomonal agent for the treatment of mucoid-producing Pseudomonas in acute respiratory infection.
No preview · Article · Feb 2000 · Journal of Antimicrobial Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: While a time-kill methodology noted no appreciable improvement in bactericidal activity with the addition of azithromycin (AZM) to a ceftazidime (CAZ) regimen, data from the murine pneumonia model showed that the addition of AZM significantly improved survival compared to treatment with CAZ alone. These data suggest that AZM might be a useful adjunctive therapy in the management of pneumonia resulting from mucoid isolates of Pseudomonas aeruginosa.
Preview · Article · Jan 2000 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Trovafloxacin pharmacokinetics were evaluated in 12 subjects with AIDS. By using a randomized design, single 200-mg doses of oral trovafloxacin and intravenous alatrofloxacin were administered. The mean absolute bioavailability was 91%. The pharmacokinetics of trovafloxacin when administered orally as the active form or intravenously as the prodrug (alatrofloxacin) are not altered in subjects with AIDS compared to those in healthy adults.
Full-text · Article · Jan 2000 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: The intracellular dispositions of clarithromycin and azithromycin in AIDS patients requiring Mycobacterium avium complex (MAC) prophylaxis were studied. The dispositions of both drugs in mononuclear and polymorphonuclear leukocytes were markedly different. Our data support the proven efficacy of these agents for MAC prophylaxis since clarithromycin and azithromycin displayed sustained intracellular concentrations which exceeded their MICs for MAC throughout the dosing periods.
Preview · Article · Oct 1999 · Antimicrobial Agents and Chemotherapy