Jerome J. Schentag

Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme.

AbstractObjective: To characterise the pharmacokinetic-pharmacodynamic relationships for linezolid efficacy.n Design and study population: Retrospective nonblinded analysis of severely debilitated adult patients with numerous comorbid conditions and complicated infections enrolled under the manufacturers’s compassionate use programme.n Methods: Patients received intravenous or oral linezolid 600mg every 12 hours. Plasma concentrations were obtained and a multicompartmental pharmacokinetic model was fitted. Numerical integration of the fitted functions provided the area under the concentration-time curve over 24 hours (AUC), the ratio of AUC to minimum inhibitory concentration (AUC/MIC) and the percentage of time that plasma concentrations exceeded the MIC (%T>MIC).n Main outcome measures: Modelled pharmacodynamic outcomes of efficacy included probabilities of eradication and clinical cure (multifactorial logistic regression, nonparametric tree-based modelling, nonlinear regression) and time to bacterial eradication (Kaplan-Meier and Cox proportional hazards regression). Factors considered included AUC/MIC, %T>MIC, site of infection, bacterial species and MIC, and other medical conditions.n Results: There were 288 cases evaluable by at least one of the efficacy outcomes. Both %T>MIC and AUC/MIC were highly correlated (Spearman r2 = 0.868). In our analyses, within specific infection sites, the probability of eradication and clinical cure appeared to be related to AUC/MIC (eradication: bacteraemia, skin and skin structure infection [SSSI], lower respiratory tract infection [LRTI], bone infection; clinical cure: bacteraemia, LRTI) and %T>MIC (eradication: bacteraemia, SSSI, LRTI; clinical cure: bacteraemia, LRTI). Time to bacterial eradication for bacteraemias appeared to be related to the AUC, %T>MIC and AUC/ MIC. For most sites, AUC/MIC and %T>MIC models performed similarly. Conclusions: Higher success rates for linezolid may occur at AUC/MIC values of 80–120 for bacteraemia, LRTI and SSSI. Chance of success in bacteraemia, LRTI and SSSI also appear to be higher when concentrations remain above the MIC for the entire dosing interval.

Changes in antimicrobial agent usage resulting from interactions among clinical pharmacy, the infectious disease division, and the microbiology laboratory

Rapid reporting of culture and susceptibility data is the first of several important steps in the successful management of infected patients. As has been said many times, rapidly reported data are of little value unless the patient directly benefits. Benefit requires better overall communication and an action plan linked to timely use of these results. In 1989 the Millard Fillmore Hospital Antibiotic Review Committee developed and implemented a prototype approach to hospital wide antimicrobial management. The formulary was revised and the drug use evaluation process modified to enhance effectiveness and to lower the cost of therapy and inventory. Clinical pharmacy antimicrobial agent management specialists were then recruited to individualize patient treatments to the isolated pathogens in conjunction with the Division of Infectious Diseases. To provide the clinical pharmacy specialists with rapid and clinically useful information, a real-time computer link was created between the pharmacy (antibiotic orders) and the microbiology laboratory (culture results). Customized software was implemented to screen all patients automatically for mismatches between pathogens and drugs, or to screen for doses inappropriate to minimum inhibitory concentration or renal function. Special attention was paid to identification of opportunities to target a more appropriate narrow-spectrum regimen after culture results became available. Changes in antimicrobial regimen or dosage were made by contacting the prescribing physician. Over 90% of the recommended changes were made, and virtually all changed regimens had satisfactory clinical outcome. Real dollar expenditures for antimicrobial agents declined by >

Determinants of antibiotic-associated hypoprothrombinemia.

200,000 per year. Prior to the institution of this computerized clinical management strategy, antimicrobial purchases were rising yearly at the rate of 12%-15%. The combined efforts of clinical pharmacy, microbiology, and infectious disease personnel successfully optimized antimicrobial therapy on a hospital wide basis. Antimicrobial agent optimization improved patient outcome, and the cost savings more than covered the costs of the program personnel and software.

Once‐Daily Cefepime Versus Ceftriaxone for Nursing Home–Acquired Pneumonia

Hypoprothrombinemia is a relatively uncommon event in the hospitalized patient. When it does occur, it often is associated with surgery, dietary vitamin K deficiency, renal dysfunction, malignancy, and broad‐spectrum antibiotic therapy. Several mechanisms have been proposed to account for antibiotic‐associated hypoprothrombinemia, including eradication of gastrointestinal bacteria, direct inhibition of vitamin K‐dependent coagulation, and indirect inhibition of coagulation. The anecdotal reports and comparative studies of antibiotic‐associated hypoprothrombinemia were reviewed; these usually implicated broad‐spectrum or the use of several antibiotics. The increased frequency of hypoprothrombinemia associated with moxalactam and cefoperazone also raises questions about the role of their N‐methylthiotetrazole (NMTT) side chains. The hypoprothrombinemia associated with NMTT antibiotics does not occur in healthy volunteers and is rare in patients without complicating conditions. Although NMTT inhibits vitamin K‐dependent carboxylation in vitro, the parent cephalosporins do not. It is not clear whether NMTT‐containing antibiotics liberate sufficient amounts of NMTT in vivo to antagonize clotting in patients. Thus, although moxalactam, and possibly cefoperazone, may in some cases be responsible for increases in prothrombin time, the most important question for further study is whether the newer NMTT‐containing antiobiotics pose a risk of hypoprothrombinemia that is greater than that of antibiotics lacking this side chain.

Assessing Antibacterial Pharmacoeconomics in the Intensive Care Unit

OBJECTIVES: To compare once‐daily intramuscular cefepime with ceftriaxone controls.

Effect of protein binding on cefmenoxime steady‐state kinetics in critical patients

SummaryIntensive care units (ICUs) represent areas of high use of antibacterials and other pharmacy goods and services. Many institutions view their ICUs as a target for drug-use surveillance and cost-containment programmes. Economic assessment of antibacterial interventions in the ICU should include all direct costs and patient outcomes. Nonetheless, many of these institutions focus their efforts at reducing antibacterial costs without considering the consequences of these actions. It is possible that devoting more resources to antibacterials can have an overall positive economic impact if more appropriate antibacterial use reduces length of stay, decreases bacterial resistance or lowers frequency of adverse complications.Two consequences of antibacterial use which can result in substantial economic burdens to institutions are drug-induced complications (toxicities and adverse events) and the development of antibacterial-resistant organisms. These events are logical targets for performing pharmacoeconomic studies to evaluate appropriate and inappropriate antibacterial use. Either of these problems can increase length of stay, which is the single most important variable influencing the overall cost of patient care.The primary goal of patient care is to hasten patients’ clinical improvement. This will result in decreased antibacterial acquisition costs, decreased lengths of leu and hospital stays, and ultimately decreased consumption of hospital resources. These can be accomplished by using strategies to guide antibacterial use in order to reduce failures, adverse events, toxicity and antimicrobial resistance.

Direct costs in patients hospitalised with community-acquired pneumonia after non-response to outpatient treatment with macrolide antibacterials in the US.

The effect of protein binding on cefmenoxime steady‐state kinetics was studied in 20 critical patients with gram‐negative pneumonia. Sixteen patients were given 1 gm cefmenoxime every 6 hr, two received 2 gm every 6 hr, and two received 2 gm every 8 hr. Serum protein binding was measured by equilibrium dialysis. Assays were by HPLC. Serum cefmenoxime concentration‐time data were characterized by a model‐independent method based on statistical moment theory. Despite varying renal function in patients, mean cefmenoxime serum concentration‐time curves for all three dosing regimens were closely aligned, reflecting successful empiric dosage adjustment. Terminal phase t½ ranged from 0.8 to 2.9 hr and was significantly related to creatinine clearance. Cefmenoxime total clearance was significantly related to both λz (2.303 times the slope of the terminal portion of the log‐concentration–time curve) and creatinine clearance (CCr). Plasma clearance of free cefmenoxime was more strongly correlated with CCr than the clearance of total cefmenoxime. Drug recovery from 24‐hr urine collections at steady state was 76.9 ± 19.8% of the daily dose (mean ± SD, n = 13). Cefmenoxime protein binding in patients differed markedly from normal values. A regression equation derived from data on 11 cephalosporins appeared to predict total volume of distribution in the steady state (Vdss‐Total) from the fraction of unbound drug accurately. Since cefmenoxime has a high therapeutic index, no clinical consequences are expected to result from variation in protein binding. Observed differences in protein binding between patients and normal subjects could have clinical consequences for highly bound acidic drugs that, unlike cefmenoxime, have narrow therapeutic indices.

Efficacy of a Methylphenidate Transdermal System Versus t.i.d. Methylphenidate in a Laboratory Setting

AbstractIntroduction: Antibacterial cost-containment programmes emphasise the use of narrow-spectrum generic agents whenever possible. The use of these agents is driven by their lower purchase prices; the consequences of treatment failure are rarely considered. This study was conducted to identify the costs of treating patients hospitalised with community-acquired pneumonia (CAP) associated with Streptococcus pneumoniae following failure to respond to outpatient treatment with macrolide antibacterials.n Methods: A multicentre, retrospective, observational study was performed in patients with CAP due to S. pneumoniae who were admitted to 31 North American hospitals following a lack of response to ≥2 days of outpatient treatment with a macrolide antibacterial. Direct medical costs (year 2004 values) of infection-related hospital resources, including antibacterials (purchase, preparation, dispensing, administration and monitoring), diagnostic tests, therapeutic procedures, treatment of adverse events and therapeutic failures, and hospitalisation per diem (ward, critical care and ventilator days), were analysed. Total hospital costs were then compared with standard diagnosis-related group (DRG) reimbursement.n Results: A total of 122 patients were enrolled. Patients were frequently bacteraemic (52%) and infected with macrolide-resistant strains of S. pneumoniae (71%). Initial inpatient antibacterial treatment was not successful in 17 patients (14%) and seven patients (5.7%) died. The mean length of stay was 8.7 days (SD 7) including 1.3 days (SD 2.9) in a critical care unit and 1.4 days (SD 4.4) of mechanical ventilation. The mean cost of hospitalisation was

Telemetry capsule and process

US12 678 (SD 13 346) but standard DRG reimbursement averaged only

Sampling capsule and process

US8 634.n Conclusions: Patients who do not respond to outpatient treatment with a macrolide antibacterial and who are subsequently hospitalised with CAP caused by S. pneumoniae are likely to be infected with a non-susceptible strain, are frequently bacteraemic, are at an increased risk for mortality compared with previously published estimates in patients with CAP due to S. pneumoniae, and incur hospital costs that far exceed standard DRG reimbursement for CAP.