Manjunath P. Pai

Time to Initiation of Fluconazole Therapy Impacts Mortality in Patients with Candidemia: A Multi-Institutional Study

BACKGROUND Inadequate antimicrobial treatment is an independent determinant of hospital mortality, and fungal bloodstream infections are among the types of infection with the highest rates of inappropriate initial treatment. Because of significant potential for reducing high mortality rates, we sought to assess the impact of delayed treatment across multiple study sites. The goals our analyses were to establish the frequency and duration of delayed antifungal treatment and to evaluate the relationship between treatment delay and mortality. METHODS We conducted a retrospective cohort study of patients with candidemia from 4 medical centers who were prescribed fluconazole. Time to initiation of fluconazole therapy was calculated by subtracting the date on which fluconazole therapy was initiated from the culture date of the first blood sample positive for yeast. RESULTS A total of 230 patients (51% male; mean age +/- standard deviation, 56 +/- 17 years) were identified; 192 of these had not been given prior treatment with fluconazole. Patients most commonly had nonsurgical hospital admission (162 patients [70%]) with a central line catheter (193 [84%]), diabetes (68 [30%]), or cancer (54 [24%]). Candida species causing infection included Candida albicans (129 patients [56%]), Candida glabrata (38 [16%]), Candida parapsilosis (25 [11%]), or Candida tropicalis (15 [7%]). The number of days to the initiation of antifungal treatment was 0 (92 patients [40%]), 1 (38 [17%]), 2 (33 [14%]) or > or = 3 (29 [12%]). Mortality rates were lowest for patients who began therapy on day 0 (14 patients [15%]) followed by patients who began on day 1 (9 [24%]), day 2 (12 [37%]), or day > or = 3 (12 [41%]) (P = .0009 for trend). Multivariate logistic regression was used to calculate independent predictors of mortality, which include increased time until fluconazole initiation (odds ratio, 1.42; P < .05) and Acute Physiology and Chronic Health Evaluation II score (1-point increments; odds ratio, 1.13; P < .05). CONCLUSION A delay in the initiation of fluconazole therapy in hospitalized patients with candidemia significantly impacted mortality. New methods to avoid delays in appropriate antifungal therapy, such as rapid diagnostic tests or identification of unique risk factors, are needed.

Antimicrobial Dosing Considerations in Obese Adult Patients

As obesity continues to increase in prevalence throughout the world, it becomes important to explore the effects that obesity has on antimicrobial disposition. Physiologic changes in obesity can alter both the volume of distribution and clearance of many commonly used antimicrobials. These changes often present challenges such as estimation of creatinine clearance to predict drug clearance. Although these physiologic changes are increasingly being characterized, few studies assessing alterations in tissue drug distribution and the effects of obesity on antimicrobial pharmacokinetics have been published. The available data are most plentiful for antibiotics that historically have included clinical therapeutic drug monitoring. These data suggest that dosing of vancomycin and aminoglycosides be based on total body weight and adjusted body weight, respectively. Obese patients may require larger doses of β‐lactams to achieve similar concentrations as those of patients who are not obese. Fluoroquinolone pharmacokinetics are variably altered by obesity, which prevents a uniform approach. Data on the pharmacokinetics of drugs that have activity against gram‐positive organisms— quinupristin‐dalfopristin, linezolid, and daptomycin—reveal that they are altered in the presence of obesity, but more data are needed to solidify dosing recommendations. Limited data are available on nonantibacterials. An understanding of the physiologic changes in obesity and the available literature on specific antibiotics is valuable in providing a framework for rational selection of dosages in this increasingly common population of obese patients.

The Origin of the “Ideal” Body Weight Equations

OBJECTIVE: To provide a historical perspective on the origin and similarity of the “ideal” body weight (IBW) equations, and clarify the terms ideal and lean body weight (LBW). DATA SOURCES: Primary and review literature were identified using MEDLINE (1966–November 1999) and International Pharmaceutical Abstracts (1970–November 1999) pertaining to ideal and lean weight, height–weight tables, and obesity. In addition, textbooks and relevant reference lists were reviewed. DATA EXTRACTION: All articles identified through the data sources were evaluated. Information deemed to be relevant to the objectives of the review were included. DATA SYNTHESIS: Height–weight tables were generated to provide a means of comparing a population with respect to their relative weight. The weight data were found to correlate with mortality and resulted in the use of the terms desirable or ideal to describe these weights. Over the years, IBW was interpreted to represent a “fat-free” weight and thus was used as a surrogate for LBW. In addition, the pharmacokinetics of certain drugs were found to correlate with IBW and resulted in the use of IBW equations published by Devine. These equations were consistent with an old rule that was developed from height–weight tables to estimate IBW. Efforts to improve the IBW equations through regression analyses of height–weight data resulted in equations similar to those published by Devine. CONCLUSIONS: The similarity between the IBW equations was a result of the general agreement among the various height–weight tables from which they were derived. Therefore, any one of these equations may be used to estimate IBW.

Vancomycin: We Can't Get There From Here

BACKGROUND We sought to characterize the pharmacodynamic profile of the more intensive vancomycin dosing regimens currently used in response to the recent vancomycin guidelines. METHODS A series of Monte Carlo simulations was performed for vancomycin regimens ranging from .5 g intravenous (IV) Q12H to 2 g IV Q12H. The probability of achieving an AUC/MIC ratio ≥ 400 for each dosing regimen was calculated for minimum inhibitory concentrations (MICs) from .5 to 2 mg/L. The risk of nephrotoxicity for each regimen was derived from a previously published vancomycin trough-nephrotoxicity logistic regression function. Restricted analyses were performed that only included subjects with troughs between 15 and 20 mg/L. RESULTS At a MIC of 2 mg/L, even the most aggressive dosing regimen considered (2 g every 12 h) only yielded a probability of target attainment (PTA) of 57% while generating a nephrotoxicity probability upward of 35%(.) At a MIC of 1 mg/L, ≥3 g per day provided PTA in excess of 80% but were associated with unacceptable risks of nephrotoxicity. In the restricted analyses of subjects with troughs between 15 and 20 mg/L, all regimens produced a PTA of 100% at MICs ≤1 mg/L. The PTA was variable among the regimens at a MIC of 2 mg/L and was highly dependent on the total daily dose administered. CONCLUSIONS This study indicates that vancomycin may not be useful for treating serious methicillin-resistant Staphylococcus aureus (MRSA) infections with MIC values > 1 mg/L where PTA is questionable. Since an AUC/MIC ratio ≥ 400 is target associated with efficacy, one should consider incorporating computation of AUC when monitoring vancomycin.

Association of Fluconazole Area under the Concentration-Time Curve/MIC and Dose/MIC Ratios with Mortality in Nonneutropenic Patients with Candidemia

ABSTRACT The present study tested in vitro susceptibility of Candida bloodstream isolates to fluconazole to determine if the ratio of the fluconazole area under the concentration-time curve (AUC) or weight-normalized daily dose (dosewn) to MIC correlated with mortality. Fluconazole susceptibility and outcome data were determined for 77 patients with a positive Candida blood culture between 2002 and 2005. The most commonly isolated Candida species were C. albicans (64%), C. glabrata (14%), C. parapsilosis (8%), C. tropicalis (6%), and C. lusitaniae (4%). Only two isolates were classified as fluconazole resistant by the CLSI M27-A2 method. Fluconazole MICs were highest against C. glabrata relative to other Candida species. Overall the crude mortality assessed at hospital discharge was 19.4% (n = 15). Mortality rates by species were as follows: C. albicans, 16.3%; C. glabrata, 36.4%; C. parapsilosis, 0%; C. tropicalis, 0%; C. lusitaniae, 33.3%. A mortality rate of 50% was noted among patients infected with nonsusceptible isolates (MIC ≥ 16 μg/ml) compared to 18% for patients infected with susceptible (MIC ≤ 8 μg/ml) isolates (P = 0.17). The fluconazole dosewn/MIC (24-h) values were significantly higher for the 62 survivors (13.3 ± 10.5 [mean ± standard deviation]) compared to the 15 nonsurvivors (7.0 ± 8.0) (P = 0.03). The fluconazole AUC/MIC (24 h) values also trended higher for survivors (775 ± 739) compared to nonsurvivors (589 ± 715) (P = 0.09). These data support the dose-dependent properties of fluconazole. Underdosing fluconazole against less-susceptible Candida isolates has the potential to increase the risk of mortality associated with candidemia.

Estimation of creatinine clearance in morbidly obese patients

PURPOSE Estimates of creatinine clearance (CL(cr)) based on equations and various body-size descriptors were compared with 24-hour measured CL(cr) values in morbidly obese patients. METHODS Patients age 18-75 years with a body mass index (BMI) of >/=40 kg/m(2) with stable serum creatinine values were enrolled. Covariates known to contribute to alteration in CL(cr) were used to exclude patients. Twenty-four-hour urine collection was performed to measure CL(cr). Bioelectric impedance analysis was used to estimate fat-free weight (FFW). Glomerular filtration rate was estimated using the four-variable Modification of Diet in Renal Disease (MDRD4) equation. CL(cr) was estimated using the Cockcroft-Gault and Salazar-Corcoran methods using total body weight (TBW). Body-size descriptors, such as ideal body weight (IBW), adjusted body weight (ABW), and lean body weight (LBW), and FFW were substituted in the Cockcroft-Gault equation to generate additional estimates of CL(cr). RESULTS Fifty-four patients (mean +/- S.D. age, 48.4 +/- 12.9 years; TBW, 142.3 +/- 41.7 kg; BMI, 50.5 +/- 12.6 kg/m(2)) completed the study. All three equations were biased in their estimation of CL(cr). Use of MDRD4 and IBW in the Cockcroft-Gault equation underestimated CL(cr), while the Salazar-Corcoran equation and use of TBW or ABW in the Cockcroft-Gault equation overestimated this value. Substitution of fat-free weight or LBW in the Cockcroft-Gault equation provided unbiased estimates of CL(cr). CONCLUSION An LBW estimate, based on TBW and BMI, incorporated into the Cockcroft-Gault equation provided an unbiased, relatively precise, accurate, and clinically practical estimate of 24-hour measured CL(cr) in morbidly obese patients.

Risk Factors Associated with the Development of Infection with Linezolid- and Vancomycin-Resistant Enterococcus faecium

This retrospective cohort study revealed that linezolid resistance in vancomycin-resistant Enterococcus faecium was dependent on prior linezolid exposure and duration of linezolid therapy. These strains of E. faecium were resistant to the entire class of oxazolidinones.

Estimating the Glomerular Filtration Rate in Obese Adult Patients for Drug Dosing

One-third of adult Americans are currently classified as obese. Physiologic changes associated with obesity can potentially alter the clearance of commonly used drugs. Clearance of certain drugs by the kidneys occurs primarily through glomerular filtration and tubular secretion. Obesity has been associated with glomerular hyperfiltration, whereas obesity-related effects on tubular secretion are not well characterized. Estimation of the glomerular filtration rate (GFR) is currently performed using serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. However, drug dosing guidelines are often based on creatinine clearance (CLcr) using the Cockcroft-Gault equation as a surrogate of GFR. There is a lack of consensus on the most appropriate method for estimation of GFR or CLcr in patients with obesity. The controversy relates to the use of 2 body size descriptors that confound these equations. The Cockcroft-Gault equation relies on total body weight and so overestimates GFR in patients with obesity. The MDRD equation indexes GFR based on a normalized body surface area, that is, mL/min/1.73 m(2). Conversion of MDRD estimated GFR to non-normalized body surface area overestimates GFR in patients with obesity. The current review explores current approaches and controversies to estimation of GFR and CLcr among obese patients in clinical practice. The role of the alternate body size descriptor, lean body weight to estimate CLcr in obese patients is reviewed.

Drug Dosing Based on Weight and Body Surface Area: Mathematical Assumptions and Limitations in Obese Adults

The average weight of adults in the United States has increased by 25 pounds (11 kg) over the past 50 years, with a marginal change in height. Drugs are generally dosed according to one of three approaches: fixed dosing, weight‐based dosing, or body surface area–based dosing. Dosing based on body weight or body surface area assumes that drug pharmacokinetic parameters increase in proportion with increasing body size. In contrast, dosing drugs on a fixed basis assumes that drug pharmacokinetic parameters do not increase with body size. Unfortunately, early stages of clinical drug development tend to include adults within a narrow range of body size. This study population does not reflect the current U.S. population distribution and does not permit evaluation of the correct relationship between body size and drug clearance. As a consequence, a weight‐based or body surface area–based dosing regimen defined during drug development may not be applicable to U.S. patient populations. These dosing strategies are more likely to result in drug overexposure (weight‐based approach) or underexposure (body surface area–based approach) among obese patients. Alternate weight descriptors such as ideal body weight, adjusted body weight, fat‐free weight, and lean body weight are used to prevent drug overexposure with weight‐based dosing, but their benefits and limitations must be understood. Reappraisal of the drug dosing paradigm is needed in this era of rising obesity; however, until drug‐specific reviews can be performed, clinical studies must include patients at the extremes of the weight continuum to ensure applicable dose extrapolation for body size.

Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin

ABSTRACT The present study characterized the single-dose pharmacokinetics of daptomycin dosed as 4 mg/kg of total body weight (TBW) in seven morbidly obese and seven age-, sex-, race-, and serum creatinine-matched healthy subjects. The glomerular filtration rate (GFR) was measured for both groups following a single bolus injection of [125I]sodium iothalamate. Noncompartmental analysis was used to determine the pharmacokinetic parameters, and these values were normalized against TBW, ideal body weight (IBW), and fat-free weight (FFW) for comparison of the two groups. All subjects enrolled in this study were female, and the mean (±standard deviation) body mass index was 46.2 ± 5.5 kg/m2 or 21.8 ± 1.9 kg/m2 for the morbidly obese or normal-weight group, respectively. The maximum plasma concentration and area under the concentration-time curve from dosing to 24 h were approximately 60% higher (P < 0.05) in the morbidly obese group than in the normal-weight group, and these were a function of the higher total dose received in the morbidly obese group. No differences in daptomycin volume of distribution (V), total clearance, renal clearance, or protein binding were noted between the two groups. Of TBW, FFW, or IBW, TBW provided the best correlation to V. In contrast, TBW overestimated GFR through creatinine clearance calculations using the Cockcroft-Gault equation. Use of IBW in the Cockcroft-Gault equation or use of the four-variable modification of diet in renal disease equation best estimated GFR in morbidly obese subjects. Further studies of daptomycin pharmacokinetics in morbidly obese patients with acute bacterial infections and impaired renal function are necessary to better predict appropriate dosage intervals.