What is a new drug worth? An innovative model for performance-based pricing.

This article focuses on a novel method to derive prices for new pharmaceuticals by making price a function of drug performance. We briefly review current models for determining price for a new product and discuss alternatives that have historically been favoured by various funding bodies. The progressive approach to drug pricing, proposed herein, may better address the views and concerns of multiple stakeholders in a developed healthcare system by acknowledging and incorporating input from disparate parties via comprehensive and successive negotiation stages. In proposing a valid construct for performance-based pricing, the following model seeks to achieve several crucial objectives: earlier and wider access to new treatments; improved transparency in drug pricing; multi-stakeholder involvement through phased pricing negotiations; recognition of innovative product performance and latent changes in value; an earlier and more predictable return for developers without sacrificing total return on investment (ROI); more involved and informed risk sharing by the end-user.

Control of epidemic group A meningococcal meningitis in Nepal.

During the first six months of 1983, an epidemic of serogroup A meningococcal meningitis occurred in the Kathmandu valley of Nepal, resulting in 875 cases and 95 deaths. The annual attack rate was 103 cases per 100,000 population, with a peak attack rate occurring in April. Epidemic meningococcal disease had not been recognized previously in Nepal. Early in 1984, a review of hospital-based data on pyogenic meningitis in Kathmandu showed three times as many cases per month compared with the same period the previous year, suggesting that a recurrent epidemic was unfolding. Beginning in February 1984, a vaccination campaign directed at a high-risk target population of people aged 1-24 years was launched; over 329,000 doses of bivalent A/C meningococcal vaccine were given, achieving approximately 64% coverage of the target population. A dramatic decline in the number of new meningitis cases occurred coincident with the initiation of the mass vaccination campaign. This experience demonstrates that it is possible, with appropriate surveillance efforts, to detect an evolving epidemic of meningococcal disease early in its course and to institute control measures in advance of the expected epidemic peak.

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.

Comparison of bactericidal activity after multidose administration of clarithromycin, azithromycin, and ceruroxime axetil against Streptococcus pneumoniae.

The objective of this study was to compare the duration of serum bactericidal activity (SBA) for clarithromycin, azithromycin, and cefuroxime axetil in 12 young healthy volunteers after 5 days of therapy (dosed to steady-state) against two strains each of penicillin (PCN)-susceptible, -intermediate, and -resistant Streptococcus pneumoniae. This was a randomized, 3-way crossover study. All isolates were susceptible to clarithromycin (MICs 0.125 mg/l) and azithromycin (MICs 0.25-0.5 mg/l), while cefuroxime axetil susceptibilities correlated with PCN. Results showed that SBA was maintained for 100% of the dosing interval for clarithromycin and 50-100% for azithromycin regardless of PCN susceptibility when standard doses were employed. Cefuroxime axetil was active only against the PCN-susceptible isolate for 50% of the dosing interval, indicating that it should only be used for PCN-susceptible S. pneumoniae.

Pharmacodynamics of ceftriaxone and cefixime against community-acquired respiratory tract pathogens.

Over the last decade or so there has been a growing interest in routes of antimicrobial administration other than by the conventional intravenous route for institutionalized patients and for some outpatients. Both oral (PO) and intramuscular (IM) routes of administration are less costly than giving antimicrobial agents by vein (IV). In addition, fewer complications such as catheter-related sepsis and phlebitis are associated with non-IV routes of administration. Furthermore, a reduced-dosage, reduced-volume IM administration of ceftriaxone may provide a tolerable route of administration and equivalent bactericidal activities compared with higher dose IV ceftriaxone. The purpose of this study was to determine the time that the drug concentration remained in excess of the minimum inhibitory concentration (MIC) (T > MIC) and the duration of bactericidal activities of ceftriaxone one gram administered IV, ceftriaxone 250 mg given IM and cefixime 400 mg given orally against clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in adult volunteers. Single doses of each agent were administered and serum concentrations were collected over the standard dosing period of 24 h for all study regimens. Ceftriaxone, regardless of route of administration and dose, resulted in bactericidal activities and T > MIC for 100% of the dosing period for S. pneumoniae, H. influenzae, and M. catarrhalis. Cefixime maintained at least 50% T > MIC and bactericidal activity against both isolates each of H. influenzae and M. catarrhalis. Against both isolates of S. pneumoniae, cefixime achieved T > MIC for at least 50% of the dosing period, but did not maintain bactericidal activity. Reduced dose ceftriaxone given IM seems to be a viable alternative to ceftriaxone IV if the pathogen, susceptibility and infection site are known. Based on T > MIC exceeding 50% of the dosing interval, cefixime would be considered an effective alternative to IV therapy against common respiratory tract pathogens. Clinical studies need to be conducted to confirm these findings.

Comparative efficacies of levofloxacin and ciprofloxacin against Streptococcus pneumoniae in a mouse model of experimental septicaemia.

The in vivo efficacies of levofloxacin and ciprofloxacin were compared against three clinical isolates of Streptococcus pneumoniae, using a mouse protection model. Two strains (SP 22 and SP 28) were penicillin-sensitive while one strain (SP 46) was penicillin-resistant. Each strain had identical susceptibility to both drugs. Using mice with renal impairment induced by uranyl nitrate injection, the elimination half-life of each antibiotic was prolonged to approximate human pharmacokinetic profiles of the drugs. The dosing regimen of each drug that yielded serum levels in mice which mimic human therapeutic concentrations of the drugs, were designed. One hour after intraperitoneal inoculation with minimum lethal dose of each strain, either levofloxacin at a dosing regimen of 10.6 mg/kg every 8 h or ciprofloxacin at 9.5 mg/kg every 8 h was subcutaneously administered for a total of six or 15 doses. In treatment, monitored daily for 5-8 days, levofloxacin resulted in higher survival compared with ciprofloxacin for the three strains. For example, percent survival following levofloxacin treatment recorded at day 4 postinfection with SP 22, SP 28 and SP 46 were 41, 90 and 30%, respectively, while the corresponding values after ciprofloxacin treatment were 27, 75 and 16%, respectively. However, statistical analysis did not reveal a significant difference (p > 0.05). The lack of significant difference observed in the efficacies of both drugs reflected the comparability of their 24-h AUC/MIC ratios. It is suggested that, with some strains of S. pneumoniae, the efficacy of levofloxacin may be equivalent to that of ciprofloxacin in the treatment of systemic pneumococcal infections caused by susceptible strains of the organism.

Clinical use of the fluoroquinolones.

The appetite for modification to the basic quinolone nucleus has grown logarithmically since the first quinolone was employed in clinical practice. Important structural refinements have led to expanded microbiologic activity, optimal pharmacokinetics, and increased safety profiles. The practicing clinician and researcher may glean considerable information from the quinolone structure with regard to microbiologic spectra and safety before administering these agents to patients. Although some toxicities can be ominously predictable, such as with the so-called high-risk quinolones (e.g., double-halogenated and trifluorinated quinolones), clinicians must rely on animal models of toxicity and clinical trial data to discern other toxicities (e.g., Q-Tc interval prolongation). A few quinolones enjoy a relatively clean safety profile and are well tolerated (e.g., gatifloxacin, levofloxacin, ciprofloxacin). Other quinolones may be associated with significant collateral system toxicity during therapy; however, under certain conditions, albeit rare, their potential for benefit may outweigh the existing risk. Clinafloxacin, for use in the management of lung infections caused by multiply resistant B. cepacia in cystic fibrosis patients, is an example of a risk that may be outweighed by its therapeutic benefit. Because there are many treatment alternatives within the clinician's armamentarium, the obligation is to select the safest, most therapeutically effective, and most cost-effective agent that is available. In addition to increasing mortality and morbidity, the development of toxicity or an adverse event during therapy may compromise the immediate effectiveness of treatment as well as affect the cost of the patient's care significantly. With the immediate abundance of quinolones available for use, the safest, most effective, and best-tolerated agents will likely emerge as the most appropriate therapeutic choices when a quinolone is indicated.

Antimicrobial pharmacodynamics.

The ultimate goal of antimicrobial therapy is to provide the best possible outcomes for patients. For this to occur, the clinician should be cognizant of many clinical, microbiologic, pharmacologic, and epidemiologic data as well as fundamental pharmacodynamic concepts. An understanding of pharmacodynamic principles is essential; it forms the scientific basis for the design of dosing strategies that maximize clinical efficacy and minimize toxicity. In the 1990s, data accumulated from in vitro models of infection, animal models of infection, healthy volunteer studies, and clinical trials that have expanded knowledge on how drugs best kill microorganisms. This knowledge has enabled clinicians to establish the best modes of antibiotic administration to maximize the killing of microorganisms and to optimize clinical outcomes.

Risk assessment for antimicrobial agent-induced QTc interval prolongation and torsades de pointes.

Over the past several years a multitude of new pharmaceutical agents have been released to the market. Several of them were withdrawn altogether or their use severely restricted to certain indications due to unexpected adverse events, including fatalities. Progress in developing new compounds clearly has surpassed our technology, in some cases, to measure and predict certain toxicities. Prolongation of the QT interval, which may lead to potentially life-threatening ventricular arrhythmias such as torsades de pointes, is one example. Regulatory agencies such as the Food and Drug Administration are increasing standards by which drugs are evaluated for cardiac toxicity related to QT interval prolongation. It is imperative that clinicians be knowledgeable of the risk factors for QT prolongation and avoid the use of culpable agents in patients at risk for QT prolongation.

Ceftibuten: an overview.

Ceftibuten is an orally active third-generation cephalosporin that exhibits good microbiologic activity against many gram-negative and select gram-positive organisms. It is stable against plasmid-mediated beta-lactamases, including extended-spectrum beta-lactamases. Ceftibuten has been shown to be effective in the treatment of upper and lower respiratory tract infections and, although not approved indications, complicated and uncomplicated urinary tract infections in both adults and children. It is readily absorbed (75-90%) after oral administration, with peak serum levels of 17 microg/ml in healthy volunteers. Its half-life is 2.5 hours in healthy volunteers and is increased in elderly patients to approximately 3.2 hours. Elimination occurs primarily through the kidneys, requiring dosage adjustments to be made when creatinine clearance falls below 50 ml/minute. The drug's safety profile is favorable and similar to that of most other cephalosporins. Based on pharmacokinetic information and clinical trial data, ceftibuten can be dosed once/day for most infections. It is an alternative to other currently available antimicrobial agents in the treatment of indicated upper and lower respiratory tract infections.

Antibiotic use in the critical care unit.

The antimicrobial management of patients in the critical care unit is complex. Not only must the clinician be familiar with a number of clinical, microbiological, pharmacological, and epidemiological observations but also fundamental pharmacodynamic concepts. It is an understanding of these concepts that forms the basis for the design of dosing strategies that maximize clinical efficacy and minimize toxicity. Antimicrobial selection is further complicated by the plethora of new antimicrobial agents available with varying clinical utility. Nowhere is this more evident than in the quinolone class of antibiotics. To aid the clinician in differentiating between quinolones it now seems reasonable to create a classification system akin to the generation grouping applied to the cephalosporins. Our classification is based upon the pharmacodynamic principles discussed within this article.

New antibiotics in pulmonary and critical care medicine: focus on advanced generation quinolones and cephalosporins.

The primary goal in the treatment of respiratory tract infections is to provide the best possible clinical outcome for the patients. In order for this to occur, one must consider and synthesize a tremendous amount of data, much of it changing continually. Important considerations include the pharmacokinetics of the selected agent, its microbiological potency when used alone and in combination with various other agents, and the susceptibilities of the target organisms. Gram-negative bacilli remain among the most frequent cause of bacterial infection in the intensive care unit and in debilitated populations. They also have the ability to resist the best therapies. Among the topics to be discussed here are the important pharmacodynamic concepts and their role in the determination of clinical efficacy, the newer quinolone agents, newly emerging mechanisms of resistance, and recent countermeasures that have been added to the therapeutic armamentarium. In addition, specific strategies designed to combat current resistance trends supported by several recent publications will be reviewed.

In vitro synergistic activities of tobramycin and selected beta-lactams against 75 gram-negative clinical isolates.

The microdilution checkerboard technique was utilized to distinguish synergistic activity between tobramycin and four beta-lactams: piperacillin-tazobactam, ticarcillin-clavulanate, ceftazidime, and ceftriaxone. Beta-lactam-aminoglycoside combinations were tested against 75 clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumanii, Citrobacterfreundii, Serratia marcescens, and Enterobacter cloacae. Despite in vitro susceptibilities, all isolates demonstrated either synergism or indifference; no antagonism was observed. Against pathogenic gram-negative nosocomial isolates, a greater percentage of synergy was consistently observed with combination regimens containing tobramycin and piperacillin-tazobactam or ticarcillin-clavulanate than with the cephalosporin-containing regimens.

Oral bioavailability and pharmacokinetics of ciprofloxacin in patients with AIDS.

Few reports on the effects of AIDS on the absorption of orally (p.o.) administered agents exist. To help fill this informational gap, we administered ciprofloxacin to 12 patients with AIDS by two dosing regimens (400 mg given intravenously [i.v.] and 500 mg given p.o. every 12 h) in a randomized, crossover fashion. Pharmacokinetic parameters were determined by noncompartmental methods. Mean values (+/- standard deviations [SD]) for p.o. ciprofloxacin were as follows: peak concentration of drug in serum (Cmax), 2.94 +/- 0.51 microg/ml; time to Cmax, 1.38 +/- 0.43 h; area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 12.13 +/- 3.21 microg x h/ml; and half-life (t(1/2)), 3.86 +/- 0.48 h. Mean values (+/- SD) for i.v. ciprofloxacin were as follows: Cmax, 3.61 +/- 0.82 microg/ml; time to Cmax, 1.0 h; AUC(0-12), 11.92 +/- 2.92 microg x h/ml; and t(1/2), 3.98 +/- 0.94 h. The mean percent absolute bioavailability for ciprofloxacin was calculated to be 82% +/- 13%, similar to the value for healthy volunteers. We conclude that ciprofloxacin when administered p.o. to patients with AIDS is well absorbed, as evidenced by excellent bioavailability and is not affected by gastrointestinal changes in the absence of infectious gastroenteritis and severe diarrhea.

Pharmacokinetics of rifapentine in subjects seropositive for the human immunodeficiency virus: a phase I study.

Rifapentine is undergoing development for the treatment of pulmonary tuberculosis. This study was conducted to characterize the single-dose pharmacokinetics of rifapentine and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of absorption in participants infected with human immunodeficiency virus (HIV). Twelve men and four women, mean age, 38.6 +/- 6.9 years, received a single 600-mg oral dose of rifapentine in an open-label, randomized two-way, complete crossover study. Each volunteer received rifapentine following a high-fat breakfast or during a fasting period. Serial blood samples were collected for 72 h and both rifapentine and its metabolite were assayed by a validated high-performance liquid chromatography method. Pharmacokinetics of rifapentine and 25-desacetylrifapentine were determined by noncompartmental methods. Mean (+/- the standard deviation) maximum concentrations of rifapentine in serum and areas under the curve from time zero to infinity following a high-fat breakfast were 14.09 +/- 2.81 and 373.63 +/- 78.19 micrograms/ml, respectively, and following a fasting period they were 9.42 +/- 2.67 and 256.10 +/- 86.39 micrograms. h/ml, respectively. Pharmacokinetic data from a previously published healthy volunteer study were used for comparison. Administration of rifapentine with a high-fat breakfast resulted in a 51% increase in rifapentine bioavailability, an effect also observed in healthy volunteers. Although food increased the exposure of these patients to rifapentine, the infrequent dosing schedule for the treatment of tuberculosis (e.g., once- or twice-weekly dosing) would be unlikely to lead to accumulation. Additionally, autoinduction has been previously studied and has not been demonstrated with this compound, unlike with rifabutin and rifampin. Rifapentine was well tolerated by HIV-infected study participants. The results of our study suggest that no dosage adjustments may be required for rifapentine in HIV-infected patients (Centers for Disease Control and Prevention classification A1, A2, B1, or B2) undergoing treatment for tuberculosis.