Blair Capitano

Measurement of adherence to antiretroviral medications.

Summary: Measurement of adherence may be important in determining why patients fail antiretroviral therapy. Although patient self‐report is by far the most frequently used means of assessing adherence, it overestimates adherence. However, patients who state they are nonadherent almost always are. The pill identification test is a recently described tool that may be useful in clinical practice. The best methods of adherence measurement are pill counts and electronic monitoring. Pill counts suffer from inability to record the time of consumption of therapy. Electronic monitoring enables timing of pill consumption and is the closest to a gold standard for measuring adherence. However, this is only the case if patients are carefully instructed in how to use the device, e.g., not to remove extra doses from their pill bottle. A composite adherence score has been developed that uses electronic monitoring, pill counts, and patient self‐report. The authors believe that careful measurement of adherence is essential in the assessment of a patient failing to respond to antiretroviral therapy.

Failure of Current Cefepime Breakpoints To Predict Clinical Outcomes of Bacteremia Caused by Gram-Negative Organisms

ABSTRACT For commonly encountered gram-negative bacilli, a MIC of cefepime of 8 μg/ml or less was defined by the Clinical and Laboratory Standards Institute as “susceptible” prior to the commercial release of the antibiotic. We assessed 204 episodes of bacteremia caused by gram-negative organisms for which patients received cefepime (typically 1 to 2 g every 12 h) as the primary mode of therapy. The cefepime MIC breakpoint derived by classification and regression tree (CART) software analysis to delineate the risk of 28-day mortality was 8 μg/ml. Patients infected with gram-negative organisms treated with cefepime at a MIC of ≥8 μg/ml had a mortality rate of 54.8% (17/31 died), compared to 24.1% (35/145 died) for those treated with a cefepime MIC of <8 μg/ml. The rate of mortality for those treated with a cefepime MIC of 8 μg/ml was 56.3% (9/16 died), compared to 53.3% (8/15 died) for those treated with cefepime at a MIC of >8 μg/ml. A multivariable analysis including severity of illness indices showed that treating patients with bacteremia due to gram-negative organisms with a cefepime MIC of ≥8 μg/ml was an independent predictor of mortality (P ≤ 0.001). There was no significant difference in outcome according to the dosage regimen utilized. Pharmacodynamic assessments that were presented previously would suggest that cefepime treatment (particularly a dosage of 1 g every 12 h) has a low probability of target attainment associated with successful in vivo outcome when the cefepime MIC is ≥8 μg/ml. It would appear reasonable, based on pharmacodynamic and clinical grounds, to lower the breakpoints for cefepime in countries where the cefepime dosage of 1 to 2 g every 12 h is the licensed therapy for serious infections, so that organisms with a cefepime MIC of 8 μg/ml are no longer regarded as susceptible to the antibiotic.

Cost effect of managing methicillin-resistant Staphylococcus aureus in a long-term care facility

OBJECTIVES: The purpose of this study was to measure the total consumption of resources involved in the care of a long‐term care facility (LTCF) resident infected with methicillin‐resistant Staphylococcus aureus (MRSA).

Suboptimal aminoglycoside dosing in critically ill patients.

Maximal aminoglycoside (AG) killing requires that the ratio of peak serum concentrations (Cmax) to the minimum inhibitory concentration (MIC) of the pathogen exceeds by ≥10. This has been shown to hasten resolution of infection in the general patient population. It was postulated that critically ill patients, likely to have larger intravascular volumes, are underdosed. The primary aim was to determine Cmax to MIC target attainment rate in medical intensive care unit (MICU) patients. A retrospective review of MICU patients who received at least 1 intravenous dose and serum concentration of either gentamicin or tobramycin was performed. A population pharmacokinetic model was developed, and MIC distributions for AG were used in determining the Cmax/MIC and in calculating the probability of attaining the pharmacodynamic (PD) target. One hundred two unique patients with 211 AG concentrations were analyzed to determine population pharmacokinetic parameters. Mean maximum clearance (CL) was 3.14L/h (95% confidence interval: 1.26-4.54 L/h), and mean volume of distribution (V) was 53 L (95% confidence interval: 38-66.8 L/h). Glomerular filtration rate and standardized body weight were identified as significant covariates for clearance in the final model. Standardized body weight also significantly affected V. There was only a 20% and 40% probability that patients receiving 7 mg/kg of gentamicin and tobramycin, respectively, will achieve PD target over the range of MIC distributions. Based on these data, the majority of critically ill patients would not be predicted to achieve the PD target under current dosing regimens. This may be a result of intensive care unit patients having a larger volume of distribution than reported in the literature. Future recommendations for treating gram-negative infections in the MICU population include using initial doses of 7 mg/kg of either gentamicin or tobramycin, measuring Cmax after the first dose, and determining MIC for the pathogen(s) with adjustment of subsequent doses to achieve the PD target.

Epidemiological Profile of Linezolid-Resistant Coagulase-Negative Staphylococci

BACKGROUND Surveillance studies have shown that <0.1% of coagulase-negative staphylococci are linezolid resistant; however, at our institution, 4% of such organisms were found to be resistant. We investigated the risk factors for and the epidemiological profile of linezolid-resistant coagulase-negative staphylococci. METHODS Susceptibility testing and pulsed-field gel electrophoresis were performed to analyze the genetic relatedness of both linezolid-resistant and linezolid-susceptible isolates. Clinical data were retrieved from medical records, and a case-case-control study was performed to identify unique risk factors for linezolid resistance. RESULTS Isolates recovered from 25 patients with linezolid-resistant coagulase-negative staphylococci were examined; all but 1 of the isolates were identified as Staphylococcus epidermidis, and all but 1 had a minimum inhibitory concentration of linezolid of >256 microg/mL. Pulsed-field gel electrophoresis showed that 21 (84%) of 25 linezolid-resistant isolates exhibited genetic relatedness, whereas linezolid-susceptible isolates were of diverse clones. Unique, independent predictors of linezolid resistance included receipt of linezolid in the 3 months preceding isolation of the coagulase-negative staphylococci (odds ratio, 20.6; 95% confidence interval, 5.8-73.0). CONCLUSION Linezolid-resistant coagulase-negative staphylococci have emerged at our institution and are predominately of a single clone. We believe that the most likely scenario to explain this emergence is that person-to-person spread of linezolid-resistant coagulase-negative staphylococci led to establishment of skin colonization with the strain. Subsequent use of linezolid was followed by selection of the linezolid-resistant strain, which then became the dominant skin flora. The potential for a parallel scenario involving clonal dissemination followed by selection of linezolid-resistant methicillin-resistant Staphylococcus aureus is a real possibility.

Intrapulmonary Penetration of Voriconazole in Patients Receiving an Oral Prophylactic Regimen

ABSTRACT Voriconazole penetrated well into the pulmonary epithelial lining fluid (ELF) in lung transplant patients receiving oral prophylaxis. The ELF concentrations exceeded those of the plasma, with an average ELF-to-plasma ratio of 11 (±8). A strong association between plasma and ELF concentrations (r2 = 0.95) was noted.

Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients

ABSTRACT This study was undertaken to characterize the pharmacokinetics and bioavailability of voriconazole in adult lung transplant patients during the early postoperative period, identify factors significantly associated with various pharmacokinetic parameters, and make recommendations for adequate dosing regimens. Thirteen lung transplant patients received two intravenous infusions (6 mg/kg, twice daily [b.i.d.]) immediately posttransplant followed by oral doses (200 mg, b.i.d.) for prophylaxis. Blood samples (9/interval) were collected during one intravenous and one oral dosing interval from each patient. Voriconazole plasma concentrations were measured by high-pressure liquid chromatography (HPLC). NONMEM was used to develop pharmacokinetic models, evaluate covariate relationships, and perform Monte Carlo simulations. There was a good correlation (R2 = 0.98) between the area under the concentration-time curve specific for the dose evaluated (AUC0-∞) and trough concentrations. A two-compartment model adequately described the data. Population estimates of bioavailability, clearance, Vc, and Vp were 45.9%, 3.45 liters/h, 54.7 liters, and 143 liters. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability (23.7%, n = 3) than non-CF patients (63.3%, n = 10). Bioavailability increased with postoperative time and reached steady levels in about 1 week. Vp increased with body weight. Bioavailability of voriconazole is substantially lower in lung transplant patients than non-transplant subjects but significantly increases with postoperative time. CF patients exhibit significantly lower bioavailability and exposure of voriconazole and therefore need higher doses. Intravenous administration of voriconazole during the first postoperative day followed by oral doses of 200 mg or 400 mg appeared to be the optimal dosing regimen. However, voriconazole levels should be monitored, and the dose should be individualized based on trough concentrations as a good measure of drug exposure.

Cost-Effective Approaches to the Treatment of Community-Acquired Pneumonia in the Era of Resistance

Community-acquired pneumonia (CAP) infects upwards of four million people in the US each year, of which 20% require subsequent hospitalisation. Consequently, it is a large contributor to excessive healthcare resource consumption and cost. Since the aetiology of CAP is not identified in a majority of patients, treatment is often empiric, aimed at the most common causes, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and the atypical pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila). A variety of pharmaceutical agents exist for the treatment of CAP, most notably the cephalosporin and penicillin derivatives, the macrolide/azalide antibacterials, the newer tetracyclines, and most recently the respiratory fluoroquinolones. Choosing an agent is usually related to issues such as patient compliance, adverse event profiles, and the presence of resistance. Of these, resistance seems to be the main factor today. S. pneumoniae, the most common cause of CAP, is steadily acquiring resistance to a majority of the currently available antibacterials, thus further increasing costs due to prolonged hospitalisation, treatment of relapses and the use of more expensive antibacterials.Understanding and maximising the pharmacodynamic properties of the available antibacterials will not only prevent the emergence of resistance, thus prolonging their clinical utility, but also reduce the costs associated with treating the infection through rapid symptom improvement and earlier patient discharge.Numerous methods for reducing costs in patients with bacterial infections are documented in the literature and can be applied to CAP. Choosing monotherapy instead of combination therapy can reduce costs associated with the administration of the antibacterial. Agents with longer half-lives allow for once-daily administration, which in turn, leads to improved compliance, successful outcomes, and decreased costs. Administering antibacterials to maximise their pharmacodynamics, such as with continuous infusion of β-lactams, reduces the amount of drug needed in addition to savings associated with administration and supplies. Finally, transitioning patients to oral therapy as soon as they are clinically stable can significantly reduce the length of hospital stay, which is the major contributing factor of healthcare costs. The use of a clinical pathway in an institution is the most effective way to apply these cost-saving approaches in the treatment of CAP. These pathways should be specific to each institution, thus considering the resistance rates in the area and encouraging the use of the most active, cost-effective agents to produce rapid, positive clinical outcomes.

Pharmacodynamic Assessment of Ertapenem (MK-0826) against Streptococcus pneumoniae in a Murine Neutropenic Thigh Infection Model

ABSTRACT The objective of this study was to determine the susceptibility breakpoint of a new carbapenem, ertapenem (MK-0826), against Streptococcus pneumoniae strains based on bacterial density and survival studies in a murine thigh infection model. Sixteen S. pneumoniae isolates for which MICs ranged from 0.015 to 4.0 mg/liter were tested with neutropenic ICR mice. Animals were infected with bacteria at 105 to 106 CFU per thigh and were treated with ertapenem starting at 2 h postinfection for 4 days. Ertapenem was given subcutaneously at 50 mg/kg of body weight every 6 h, which simulates the human pharmacodynamic profile (in particular, the duration of time that the concentration of free drug remains above the MIC of 2 mg/liter). At 0 and 24 h postinfection, thighs were harvested for bacterial density determination. Survival was assessed during 4 days of therapy and 3 days after the therapy. A protein binding study was conducted with mice by use of the ultrafiltration method. Protein binding in mice was approximately 95%, which is comparable to that in humans. The average change in bacterial density ranged from −0.22 to −4.4 log CFU per thigh over 24 h compared to 0-h controls. The extent of microbial eradication was dependent on the MIC for the S. pneumoniae isolate. Substantial bactericidal activities (i.e., killing of approximately 2 log CFU per thigh) were consistently observed against isolates for which MICs were ≤2 mg/liter, which also resulted in nearly 100% survival during the 4 days of drug dosing and 3 days after the therapy. Less-pronounced and highly variable bactericidal activities were detected against isolates for which the MIC was 4 mg/liter. Substantial enhancement in bactericidal activity was observed for CBA/J mice and is attributed to the contribution of the host defenses in the immunocompetent species. Assessment of the effectiveness of ertapenem by bacterial-density reduction over 24 h and by survival over 4 days of therapy in the murine thigh infection model reveals that the drug maintains maximal efficacy against S. pneumoniae isolates for which the MIC of this agent is ≤2 mg/liter.

Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid

ABSTRACT Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of <100 ×109/liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.