JoCarol McNabb

Adherence to Highly Active Antiretroviral Therapy Predicts Virologic Outcome at an Inner-City Human Immunodeficiency Virus Clinic

This studys hypothesis is that human immunodeficiency virus-infected patients in the inner city (predominantly injection drug users and ethnic minorities) do not take highly active antiretroviral therapy (HAART) as prescribed and that nonadherence leads to virologic failure. A prospective, observational, 3-month study of adherence to HAART was undertaken at an inner-city clinic. There were 40 subjects [110 subject-months]; 30 were male, 10 were female, 75% were Hispanic, 23% were African American, 68% were injection drug users, and 68% were receiving triple therapy. At 3 months, adherence, which was determined by use of the Medication Event Monitoring System (Aprex) was significantly associated with virologic success: lower virus loads were associated with a rate of adherence of >80% (P<.05). Although nonadherence predicted virologic failure, virologic success was not always predicted by adherence: 11 (27.5%) of 40 subjects with suboptimal adherence rates (<90%) had complete virologic suppression.

Continuous versus intermittent administration of ceftazidime in intensive care unit patients with nosocomial pneumonia

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.

Cost-Effectiveness of Ceftazidime by Continuous Infusion versus Intermittent Infusion for Nosocomial Pneumonia

Study Objective. To determine if continuous‐infusion ceftazidime is more cost‐effective and efficacious than intermittent infusion in patients with nosocomial pneumonia.

Streptococcus pneumoniae Response to Repeated Moxifloxacin or Levofloxacin Exposure in a Rabbit Tissue Cage Model

ABSTRACT The role of moxifloxacin and levofloxacin pharmacokinetics (PK) in antimicrobial efficacy and in the selection of fluoroquinolone-resistant Streptococcus pneumoniae strains was investigated using the rabbit tissue cage abscess model. A rabbit tissue cage was created by insertion of sterile Wiffle balls in the dorsal cervical area. Animals orally received a range of moxifloxacin or levofloxacin doses that simulate human PK for 7 days 48 h after the Wiffle balls were inoculated with fluoroquinolone-sensitiveS. pneumoniae (107 CFU). Abscess fluid was collected on a daily basis over 14 days to measure bacterial density and MICs. Moxifloxacin regimens produced a range of area under the concentration-time curve (AUC)/MIC ratios ranging from 9.2 to 444 and peak/MIC ratios ranging from 1.3 to 102. Levofloxacin doses produced AUC/MIC ratios of 5.1 to 85.5 and peak/MIC ratio of 0.9 to 14.8. Moxifloxacin at 6.5, 26, and 42 mg/kg reduced the bacterial log CFU per milliliter in abscess fluid (percentage of that in a sterile animal) by 4.2 ± 2.2 (20%), 5.8 ± 0.4 (100%), and 5.4 ± 0.4 (100%), respectively, over the dosing period. Levofloxacin at 5.5, 22, and 32 mg/kg reduced the log CFU per milliliter in abscess fluid (percentage of that in a sterile animal) by 2.8 ± 0.7 (20%), 5.1 ± 1.3 (80%), and 4.6 ± 1.3 (60%), respectively. Moxifloxacin has a greater bactericidal rate as determined by regression of log CFU versus time data. The AUC/MIC and peak/MIC ratios correlated with the efficacy of both drugs (P< 0.05). Resistance to either drug did not develop with any of the doses as assessed by a change in the MIC. In conclusion, data derived from this study show that moxifloxacin and levofloxacin exhibit rapid bactericidal activity against S. pneumoniae in vivo, and moxifloxacin exhibits enhanced bactericidal activity compared to levofloxacin, with AUC/MIC and peak/MIC ratios correlated with antimicrobial efficacy for both drugs. The development of fluoroquinolone-resistant S. pneumoniae was not observed with either drug in this model.

Pharmacokinetics and Pharmacodynamics of Continuous and Intermittent Ceftazidime during the Treatment of Nosocomial Pneumonia

AbstractObjective: This study aimed too compare the pharmacokinetic and pharmacodynamic profile of intermittent and continuously infused ceftazidime in patients with nosocomial pneumonia. Design and Setting: Prospective, randomised study set in a large community-teaching hospital. Interventions: Thirty-four patients receiving ceftazidime either as an intermittent infusion or a continuous infusion underwent blood sampling for drug concentration determinations between days 2 to 5 of therapy. In addition, at study enrolment sputum samples were obtained for Gram’s stain and culture. The minimum inhibitory concentration (MIC) of isolated organisms to ceftazidime was determined using the broth microdilution technique. Main Outcome Measures: Pharmacokinetic parameters were derived individually for each patient. The pharmacodynamic profile of ceftazidime was assessed as the duration of time the serum concentration remained above the MIC (T > MIC) of the organism(s) for each regimen. Results: Patients were well matched for demographic variables. The pharmacokinetic parameter estimates (mean ± SD) for patients receiving the intermittent infusion therapy were as follows: maximum concentration in serum 106.5 ± 34.6 mg/L; half-life 3.2 ± 2.5 hours; total body clearance (CLt) 142.5 ± 59 ml/min. The steady-state concentration with the continuous infusion regimen was 17.4 ± 6.1 mg/L, while the CLt was similar at 133.2 ± 37 ml/min. Forty-six pathogens were isolated in 27 patients. The continuous infusion regimen maximised the pharmacodynamics of ceftazidime as T > MIC was 100% of the dosage interval in all patients, whereas the intermittent infusion regimens resulted in T > MIC values of 56 to 100%. Conclusions: In critically ill patients with nosocomial pneumonia the administration of ceftazidime by continuous infusion appears to optimise the pharmacodynamic profile of this β-lactam by constantly providing concentrations in excess of the MIC of susceptible organisms over the course of therapy.

Pharmacokinetics of Hydroxyurea in Plasma and Cerebrospinal Fluid of HIV‐1‐Infected Patients

Hydroxyurea has been shown to potentiate the activity of the antiretroviral nucleoside analogs. A significant complication of AIDS is invasion of the virus into the CNS, resulting in HIV‐associated dementia (HAD). Because of the polar nature of these nucleosides and the presence of efflux pumps in the blood‐brain barrier, only low CNS drug concentrations are achieved. Introduction of hydroxyurea into the CNS may therefore increase the antiviral activity of these drugs. This study evaluates the accessibility of hydroxyurea to the CNS following oral drug administration. Twelve HIV patients received 800 mg, 1000 mg, or 1200 mg oral hydroxyurea. Cerebrospinal fluid (CSF) and plasma drug concentrations were measured over 8 hours and simultaneously fitted to a pharmacokinetic model. It was determined that CSF hydroxyurea concentrations, corresponding to those found to increase antiretroviral nucleoside activity in vitro, were achieved.

PHARMACOKINETICS OF CONTINUOUS AND INTERMITTENT CEFTAZIDIME IN INTENSIVE CARE UNIT PATIENTS WITH NOSOCOMIAL PNEUMONIA

Intensive care unit patients with nosocomial pneumonia participating in a prospective, randomized trial comparing the efficacy of intermittent infusion (II) or continuous infusion (CI) ceftazidime plus an aminoglycoside were studied. The pharmacokinetic profile of ceftazidime administered as either 2 g q8h IV or 3 g CI over 24 hours were compared. Patients (II, n = 13; CI, n = 11) were well matched for demographic variables. The mean pharmacokinetic parameters (mean ± SD) for patients receiving the q8h II dose were as follows: maximum concentration in serum, 105.3 ± 28.0 μg/mL; half-life, 1.9 ± 0.6 hours; and total body clearance (CIT), 162.8 ± 42.7 mL/min. The mean steady concentration achieved with the 3-g CI dose was 15.3 ± 4.2 μg/mL, whereas the CIT was similar at 143.6 ± 30.1 mL/min. Although clinical trial data are required to fully evaluate the efficacy of different antimicrobial administration techniques, CI therapy seems to optimize the pharmacodynamic and phar-macoeconomic profile of ceftazidime by providing adequate concentrations over the 24-hour dosing period with a reduction in the total daily dose.

Comparison of the Bactericidal Activity of Trovafloxacin and Ciprofloxacin, Alone and in Combination with Cefepime, against Pseudomonas aeruginosa

Background: Although ciprofloxacin exhibits more intense microbiological activity against Pseudomonas aeruginosa than does trovafloxacin, the clinical relevance of this observation remains questionable, particularly when the agents are combined with another antipseudomonal agent. Methods: To evaluate this further, we conducted a four-way crossover trial to compare the bactericidal activities of ciprofloxacin and trovafloxacin, alone and in combination with cefepime, against three clinical isolates of P. aeruginosa. Healthy subjects received the following regimens, dosed to steady state: trovafloxacin 300 mg/24 h; ciprofloxacin 400 mg/12 h; trovafloxacin 300 mg/24 h plus cefepime 2 g/12 h, and ciprofloxacin 400 mg/12 h plus cefepime 2 g/12 h. Serum bactericidal titers were performed with each regimen. Results: As monotherapy, the area under the bactericidal curve for ciprofloxacin exceeded that of trovafloxacin for all isolates. No significant difference in the overall degree of bactericidal activity was noted for two of three P. aeruginosa isolates for the combination regimens. Additionally, both combination regimens provided bactericidal activity for 100% of the dosing interval for all isolates. Conclusion: These results indicate that, while in vitro differences exist among these quinolones for P. aeruginosa, when a fluoroquinolone is combined with a β-lactam, this is likely to be of little clinical significance.

Comparison of azithromycin leukocyte disposition in healthy volunteers and volunteers with AIDS

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 (11309+/-2543 vs. 16650+/-6254 for PMN; 14180+/-3802 vs. 21211+/-10001 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.