In vitro-in vivo model for evaluating the antiviral activity of amprenavir in combination with ritonavir administered at 600 and 100 milligrams, respectively, every 12 hours.

The study objective was to evaluate the pharmacodynamics of amprenavir in an in vitro system, develop an exposure target for maximal viral suppression, and determine the likelihood of target attainment based on the pharmacokinetics of amprenavir and ritonavir in human immunodeficiency virus (HIV)-infected patients. Population pharmacokinetic data were obtained from 13 HIV-infected patients receiving amprenavir and ritonavir in doses of 600 and 100 mg, respectively, every 12 h. A 2,500-subject Monte Carlo simulation was performed.

Optimal sampling schedule design for populations of patients.

Generation of pharmacodynamic relationships in the clinical arena requires estimation of pharmacokinetic parameter values for individual patients. When the target population is severely ill, the ability to obtain traditional intensive blood sampling schedules is curtailed. Population modeling guided by optimal sampling theory has provided robust estimates of individual patient pharmacokinetic parameter values.

Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy.

The worldwide increase in the prevalence of multi-antibiotic-resistant bacteria has threatened the physician's ability to provide appropriate therapy for infections. The relationship between antimicrobial drug concentration and infecting pathogen population reduction is of primary interest. Using data derived from mice infected with the bacterium Pseudomonas aeruginosa and treated with a fluoroquinolone antibiotic, a mathematical model was developed that described relationships between antimicrobial drug exposures and changes in drug-susceptible and -resistant bacterial subpopulations at an infection site.

Guillain-Barré syndrome associated with immune reconstitution.

We report a case of acute Guillain-Barré syndrome (GBS) associated with a prompt and vigorous immune reconstitution and decrease in the virus load noted during treatment with a potent regimen of highly active antiretroviral therapy. We hypothesize that GBS may have been due to an aberrant immune response or an adverse drug reaction in association with preexisting peripheral neurologic disease.

Integration of population pharmacokinetics, a pharmacodynamic target, and microbiologic surveillance data to generate a rational empiric dosing strategy for cefepime against Pseudomonas aeruginosa.

Study Objective: To derive steady-state pharmacokinetic profiles of cefepime against Pseudomonas aeruginosa.

Design: Retrospective evaluation using a weighted approach based on a minimum inhibitory concentration distribution of cefepime in the United States.

Setting: Medical and surgical intensive care units.

Revaccination of healthy nonresponders with hepatitis B vaccine and prediction of seroprotection response.

Sixty healthy nonresponders were randomized to receive intramuscular (IM) high dose hepatitis B virus (HBV) vaccine versus IM standard dose HBV vaccine plus granulocyte-macrophage colony-stimulating factor (GM-CSF) at 0-2 months. Antibody to hepatitis B surface antigen was measured 1 month after each dose and 3 months after the last dose. Two regimens were equivalent in eliciting seroprotection in nonresponders.

Prevention of resistance: a goal for dose selection for antimicrobial agents.

Drug-resistant microorganisms have become a major problem around the world. In nosocomial and community settings, many important pathogens have demonstrated high-grade resistance to many of our most important agents. In addition, the adverse impact of resistance has not been limited to the bacterial realm.

Pharmacodynamics of cefepime in patients with Gram-negative infections.

We conducted a prospective, open-label study to delineate a relationship between exposure and outcomes in 36 patients treated with cefepime. Twenty patients had documented Gram-negative infections. Timed blood and urine samples were obtained at steady state to determine pharmacokinetic and pharmacodynamic parameters.

Dose proportional inhibition of HIV-1 replication by mycophenolic acid and synergistic inhibition in combination with abacavir, didanosine, and tenofovir.

Mycophenolate mofetil (MMF), a therapeutically used inhibitor of inosine monophosphate dehydrogenase is hydrolyzed to its active metabolite mycophenolic acid (MPA) in vivo. MPA exhibits anti-HIV activity in vitro. We tested MPA alone and in combination with abacavir (ABC), didanosine (DDI), lamivudine (3TC) and tenofovir (TFV) against wild-type human immunodeficiency virus type-1 (HIV-1) and nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV-1.

Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs.

Over the last decades, the interest in the relationships between the pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents has increased and, therefore, the use of PK/PD indices and expressions has spread widely. The appropriate definition and use of these parameters is a matter of controversy. This paper contains a proposal to use PK/PD expressions for antimicrobial agents and their units in a uniform manner.

Rational dose selection for a nonnucleoside reverse transcriptase inhibitor through use of population pharmacokinetic modeling and Monte Carlo simulation.

In order to choose a rational dose for GW 420867X, we first set a goal of therapy. We hypothesized that, for optimal antiretroviral activity, the trough free drug concentration should remain above the 90% effective concentration (EC90) of human immunodeficiency virus type 1. We performed population pharmacokinetic analysis on three different doses of GW 420867X (50, 100, and 200 mg).

Levofloxacin penetration into epithelial lining fluid as determined by population pharmacokinetic modeling and monte carlo simulation.

Levofloxacin was administered orally to steady state to volunteers randomly in doses of 500 and 750 mg. Plasma and epithelial lining fluid (ELF) samples were obtained at 4, 12, and 24 h after the final dose. All data were comodeled in a population pharmacokinetic analysis employing BigNPEM.

Pharmacodynamics of abacavir in an in vitro hollow-fiber model system.

Abacavir is a potent new carbocyclic nucleoside analogue. We employed our hollow-fiber pharmacodynamic modeling system to examine the antiretroviral effects of different abacavir exposures, as well as the impact of the schedule of drug administration on efficacy. Dose ranging of abacavir revealed that a concentration of four times the 50% effective concentration (EC(50)) (approximately the EC(95)) was required to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) (strain MN) either in a continuous-infusion hollow-fiber experiment or in a classical tissue culture flask experiment.

Susceptibilities of human cytomegalovirus clinical isolates to BAY38-4766, BAY43-9695, and ganciclovir.

BAY38-4766 and BAY43-9695 are nonnucleosidic compounds with activities against human cytomegalovirus (HCMV). Two phenotypic assays were used to determine the drug susceptibilities of 36 HCMV clinical isolates to the BAY compounds and ganciclovir. Using either assay, both BAY compounds at a concentration of approximately 1 microM inhibited the replication of all 36 HCMV clinical isolates, including 11 ganciclovir-resistant clinical isolates, by 50%.

Pharmacodynamic and pharmacokinetic considerations in antimicrobial selection: focus on telithromycin.

The effectiveness of empirical treatment for respiratory tract infections (RTIs) with commonly available antimicrobials is threatened by the development of microbial resistance and cross-resistance between treatments. Pharmacokinetic and pharmacodynamic profiling of antimicrobial agents is increasingly being used to select the most appropriate treatment and dosage schedules for RTIs. In addition to enhancing management strategies with existing treatments, these profiles have played a key part in identifying dosage schedules for a new family of semisynthetic antimicrobials, the ketolides.

Pharmacodynamic evaluation of RWJ-270201, a novel neuraminidase inhibitor, in a lethal murine model of influenza predicts efficacy for once-daily dosing.

We examined RWJ-270201 in a lethal model of influenza in BALB/c mice. The aim was to delineate the pharmacodynamically linked variable for the drug. Challenge was performed with influenza virus A/Shongdong/09/93 (H3N2).

Tolerance and pharmacokinetic interactions of rifabutin and azithromycin.

This multicenter study evaluated the tolerance and potential pharmacokinetic interactions between azithromycin and rifabutin in volunteers with or without human immunodeficiency virus infection. Daily dosing with the combination of azithromycin and rifabutin was poorly tolerated, primarily because of gastrointestinal symptoms and neutropenia. No significant pharmacokinetic interactions were found between these drugs.

Hollow-fiber unit evaluation of a new human immunodeficiency virus type 1 protease inhibitor, BMS-232632, for determination of the linked pharmacodynamic variable.

BMS-232632 is a potent human immunodeficiency type 1 (HIV-1) protease inhibitor with a half-life that allows for once-daily dosing. A concentration of 4 times the viral 50% effective concentration (EC(50) [i.e.

Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection.

Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including Staphylococcus aureus. We defined the pharmacodynamic parameters that determine the activity of daptomycin for S. aureus using in vitro methods and the Craig (W.

Meropenem: clinical response in relation to in vitro susceptibility.

Objective: To collate the clinical response and pathogen eradication rates for meropenem monotherapy with in vitro susceptibility of the causative pathogens.

Methods: Data were compiled from 17 randomized clinical studies that compared meropenem monotherapy with standard treatment options, often combinations. A total of 4906 pathogens from lower respiratory tract, intra-abdominal, obstetric/gynecological, skin/soft tissue, meningitis, or pediatric infections were assessed.

Fluoroquinolone pharmacodynamics: prospective determination of relationships between exposure and outcome.

By using mathematical modeling it is possible to determine relationships between drug exposure and clinical or microbiological outcome. From the early exploration of Pseudomonas aeruginosa sepsis in neutropenic rats to the prospective determination of relationships between fluoroquinolone exposure and patient outcome in multicenter clinical trials, the utility of this approach has been confirmed. This prospective development of drug concentration-effect relationships can serve as a template for other anti-infective agents.