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Combination therapy with vancomycin and piperacillin/tazobactam (TZP) has been associated with increased risk of acute kidney injury (AKI) compared with monotherapy with either agent. This retrospective, matched cohort study was conducted to assess the comparative incidence of AKI due to combination therapy in patients receiving vancomycin and TZP in combination or as monotherapy. Patients aged ≥18 years admitted to Albany Medical Center (Albany, NY) between September 2013 and August 2014 who had received therapy for at least two consecutive days were included. Patients who were pregnant, neutropenic, had AKI on admission or with cystic fibrosis were excluded. Patients were matched on baseline risk of AKI. The main outcome of interest was AKI, defined as an increase in serum creatinine of ≥0.3 mg/L or ≥50% within 48 h. Secondary outcomes evaluated were length of hospital and ICU stay and inpatient mortality associated with AKI. The risk of AKI was 7.0%, 8.5% and 26.8% in the vancomycin monotherapy, TZP monotherapy and combination groups, respectively (P0.001). In the multivariate analysis, combination therapy was independently associated with an increased odds of AKI (adjusted odds ratio = 4.406, 95% confidence interval 1.472-13.188) compared with vancomycin monotherapy. The excess risk of combination therapy was 11.3%. In this matched cohort study, there was an increased incidence of AKI in patients receiving vancomycin and TZP combination therapy. Further research is needed to determine the individual strategies to best prevent inpatient AKI in patients receiving this combination therapy.

To the Editor,Drug shortages may lead to less prescribing of medications due to needed restrictions or reduced inventory. We read with interest a report in the present journal on an antimicrobial s...

This study evaluated the predictive performance of a Bayesian PK estimation method (ADAPT V) to estimate the 24-h vancomycin area under the curve (AUC) with limited pharmacokinetic (PK) sampling in adult obese patients receiving vancomycin for suspected or confirmed Gram-positive infections. This was an Albany Medical Center Institutional Review Board-approved prospective evaluation of 12 patients. Patients had a median (95% confidence interval) age of 61 years (39 to 71 years), a median creatinine clearance of 86 ml/min (75 to 120 ml/min), and a median body mass index of 45 kg/m 2 (40 to 52 kg/m 2 ). For each patient, five PK concentrations were measured, and four different vancomycin population PK models were used as Bayesian priors to estimate the vancomycin AUC (AUC FULL ). Using each PK model as a prior, data-depleted PK subsets were used to estimate the 24-h AUC (i.e., peak and trough data [AUC PT ], midpoint and trough data [AUC MT ], and trough-only data [AUC T ]). The 24-h AUC derived from the full data set (AUC FULL ) was compared to the AUC derived from data-depleted subsets (AUC PT , AUC MT , and AUC T ) for each model. For the four sets of analyses, AUC FULL estimates ranged from 437 to 489 mg·h/liter. The AUC PT provided the best approximation of the AUC FULL ; AUC MT and AUC T tended to overestimate AUC FULL . Further prospective studies are needed to evaluate the impact of AUC monitoring in clinical practice, but the findings from this study suggest that the vancomycin AUC can be estimated with good precision and accuracy with limited PK sampling using Bayesian PK estimation software.

We report on the pharmacokinetics (PK) and pharmacodynamics (PD) of high-dose (>15 mg/kg of body weight per day) amikacin. A mean (standard deviation [SD]) maximum drug concentration in the serum ( C max ) and 24-h area under the concentration-time curve (AUC 24 ) of 101 (49.4) mg/liter and 600 (387) mg · h/liter, respectively, were observed ( n = 73) with 28.0 (8.47) mg/kg/day doses. An initial amikacin dose of 2,500 mg in adults weighing 40 kg to 200 kg with therapeutic drug monitoring to adjust the maintenance dose will optimize its PK and PD.

tudy Objective To compare the likelihood of alternative vancomycin dosing strategies based on weight, height, or body surface area (BSA) in achieving isometric vancomycin area under the serum concentration–time curve (AUC) values across the body size distribution of children and young adults. Design Maximum a posteriori probability Bayesian (MAP-Bayesian) pharmacokinetic analysis using retrospectively collected medical record data. Setting Children's hospital. Patients A total of 115 patients 1–20 years of age managed outside of the intensive care unit who were treated with vancomycin between May 1, 2011, and August 31, 2012, and had a minimum of two serum vancomycin concentration measurements. Measurements and Main Results Vancomycin dosing and concentration-time information along with demographic and laboratory data related to kidney function estimation were extracted from the patients' medical records. A previously structured one-compartment model was used to derive MAP-Bayesian estimates of pharmacokinetic system parameters for each patient. Post hoc linear and power function regression were used to compare clearance (Cl) and the volume of distribution of the central compartment (Vc) to body size descriptors (weight, height, and BSA). The relationship of the body size descriptor-indexed parameter across the body size distribution was assessed. The AUC from time 0 to 24 hours (AUC24) values associated with vancomycin dosing regimens based on weight, height, and BSA were estimated. The 115 patients (56.5% male) had a mean ± SD age, height, and weight of 9.7 ± 5.4 years, 133 ± 32.3 cm, and 38.0 ± 24.2 kg, respectively. Each patient received a minimum of four doses of vancomycin and had two to nine serum vancomycin concentration measurements, for a total of 313 measurements for all patients. Vancomycin Cl was a nonlinear function of weight and a linear-proportionate function of BSA, whereas the volume of distribution of the central compartment (Vc) was a linear-proportionate function of weight. The expected median (5th–95th percentile) AUC24 values with weight-based dosing of vancomycin 60–70 mg/kg/day were 446 (315–834) mg·hour/L and 649 (385–1165) mg·hour/L in patients weighing less than 40 kg (n=72) and those weighing 40 kg or more (n=43), respectively. In contrast, isometric AUC24 values were predicted with BSA-based dosing across the body size distribution. Conclusion BSA-based dosing is more likely than weight-based (mg/kg) dosing of vancomycin to achieve isometric AUC24 values across the body size distribution of children and young adults. Pharmacokinetic studies that compare these two vancomycin dosing strategies in children are clearly needed to validate these findings.

OBJECTIVETo evaluate time to clinical response before and after implementation of rapid blood culture identification technologies.DESIGNBefore-and-after trial.SETTINGLarge, tertiary, urban, academic health-sciences center.PATIENTSPatients >18 years old with sepsis and concurrent bacteremia or fungemia were included in the study; patients who were pregnant, had polymicrobial septicemia, or were transferred from an outside hospital were excluded.INTERVENTIONPrior to the intervention, polymerase chain reaction was used to identify Staphylococcus species from positive blood cultures, and traditional laboratory techniques were used to identify non-staphylococcal species. After the intervention, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) assay and FilmArray were also used to identify additional species. During both periods, the antimicrobial stewardship team provided prospective audit and feedback for all patients on antibiotics.RESULTSA total of 219 patients were enrolled in the study: 115 patients prior to the intervention and 104 after the intervention. The median time to clinical response was statistically significantly shorter in the postintervention group than in the preintervention group (2 days vs 4 days, respectively; P=.002). By Cox regression, the implementation of MALDI-TOF and FilmArray was associated with shorter time to clinical response (hazard ratio [HR], 1.360; 95% confidence interval [CI], 1.018–1.816). After controlling for potential confounders, the study group was not independently associated with clinical response (adjusted HR, 1.279; 95% CI, 0.955–1.713). Mortality was numerically, but not statistically significantly, lower in the postintervention group than in the preintervention group (7.6% vs 11.4%; P=.342).CONCLUSIONSIn the setting of an existing antimicrobial stewardship program, implementation of MALDI-TOF and FilmArray was associated with improved time to clinical response. Further research is needed to fully describe the effect of antimicrobial stewardship programs on time to clinical response.Infect Control Hosp Epidemiol 2016;37:916–923

Administration of vancomycin continues to be common despite perceived concerns of increased MICs, treatment failures and toxicity. In 2009, a consensus guideline was published in an effort to optimize dosing and monitoring of this useful agent. It was unique in targeting a specific antibiotic rather than a disease state or organism. However, a lack of prospective randomized double-blinded trials upon which to base guidelines was noted. In addition, several questions were raised and remain unanswered. Since guideline publication, new data has added to our understanding of the implications of aggressive dosing and subsequent monitoring. The following article discusses research published within the last 2 years.

BACKGROUND Data suggest that higher doses of vancomycin can increase the risk of nephrotoxicity. No study has been undertaken to determine the pharmacodynamic index (ie, the area under the curve [AUC] or the trough value) that best describes the relationship between vancomycin exposure and onset of nephrotoxicity. METHODS A retrospective study was conducted among patients who received vancomycin for a suspected or proven gram-positive infection during the period from 1 January 2005 through 31 December 2006 at Albany Medical Center Hospital. Patients were included in our study if they (1) were > or =18 years old, (2) had an absolute neutrophil count of > or =1000 cells/mm(3), (3) received vancomycin for >48 h, (4) had 1 vancomycin trough level collected within 96 h of vancomycin therapy, and (5) had a baseline serum creatinine level of

There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus (MRSA) infections, with vancomycin MICs at the high end of the CLSI susceptibility range. Despite this growing concern, there are limited clinical data to support this notion. To better elucidate this, a retrospective cohort study was conducted among patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and May 2007. The inclusion criteria were as follows: at least 18 years old, nonneutropenic, with an MRSA culture that met the CDC criteria for bloodstream infection, had received vancomycin therapy within 48 h of the index blood culture, and survived >24 h after vancomycin administration. Failure was defined as 30-day mortality, bacteremia ≥10 days on vancomycin therapy, or a recurrence of MRSA bacteremia within 60 days of vancomycin discontinuation. Classification and regression tree (CART) analysis identified the vancomycin MIC breakpoint associated with an increased probability of failure. During the study period, 92 patients met the inclusion criteria. The vancomycin MIC breakpoint derived by CART analysis was ≥1.5 mg/liter. The 66 patients with vancomycin MICs of ≥1.5 mg/liter had a 2.4-fold increase in failure compared to patients with MICs of ≤1.0 mg/liter (36.4% and 15.4%, respectively; P = 0.049). In the Poisson regression, a vancomycin MIC of ≥1.5 mg/liter was independently associated with failure (adjusted risk ratio, 2.6; 95% confidence interval, 1.3 to 5.4; P = 0.01). These data strongly suggest that patients with MRSA bloodstream infections with vancomycin MICs of ≥1.5 mg/liter respond poorly to vancomycin. Alternative anti-MRSA therapies should be considered for these patients.

Recent guidelines recommend vancomycin trough concentrations between 15 and 20 mg/liter. In response, some clinicians increased vancomycin dosing to ≥4 g/day. Scant data are available regarding toxicities associated with higher vancomycin doses. The purpose of this study was to examine vancomycin-associated nephrotoxicity at ≥4 g/day. To accomplish the study objective, a cohort study among a random selection of patients receiving vancomycin or linezolid between 2005 and 2006 was performed. Patients were included if they (i) were ≥18 years of age, (ii) were nonneutropenic, (iii) were on therapy for >48 h, (iv) had baseline serum creatinine levels of P = 0.001), and Kaplan-Meier analysis identified significant differences in time to nephrotoxicity for the high-vancomycin-dose cohort compared to those for groups taking the standard dose and linezolid. In the Cox model, patients taking ≥4 g vancomycin/day, a total body weight of ≥101.4 kg, estimated creatinine clearance of ≤86.6 ml/min, and intensive care unit residence were independently associated with time to nephrotoxicity. The data suggest that higher-dose vancomycin regimens are associated with a higher likelihood of vancomycin-related nephrotoxicity.

Study Objectives. To compare rates of hypoglycemia and hyperglycemia among elderly hospitalized patients with normal blood glucose concentrations at baseline who were receiving either gatifloxacin or levofloxacin, and to determine if appropriateness of their doses, according to their package inserts, was associated with hypoglycemia or hyperglycemia. Design. Retrospective cohort study. Setting. Integrated Veterans Administration (VA) health care system. Patients. Nine hundred thirty-seven elderly (≥ 65 yrs) patients with documented blood glucose levels of 65–140 mg/dl before receiving a fluoroquinolone. Measurements and Main Results. Between January 2003 and April 2004, 405 patients receiving levofloxacin met study criteria. In April 2004, gatifloxacin was substituted for levofloxacin on the formulary of this VA system. Thus, between April 2004 and December 2004, 532 patients received gatifloxacin. All blood glucose concentrations during hospitalization that were measured during fluoroquinolone therapy or within 72 hours of completion of therapy were reviewed. Demographic characteristics, comorbidities, insulin and oral hypoglycemic therapies, disease severity, blood glucose levels, and outcomes were recorded and compared between groups. The two groups were similar at baseline for all characteristics examined except previous hospitalization. In the logistic regression, gatifloxacin was independently associated with both hypoglycemia (adjusted odds ratio [AOR] 2.5, 95% confidence interval [CI] 1.2–5.7, p=0.04) and hyperglycemia (AOR 2.4, 95% CI 1.5-3.6, p

Although a growing number of studies have found a relationship between delayed appropriate antibiotic therapy and mortality, few have attempted to quantify the temporal association between delayed appropriate antibiotic therapy and mortality. This study was designed to measure the elapsed time associated with an increased risk of 30-day mortality among patients with Pseudomonas aeruginosa bacteremia. The retrospective cohort study was conducted among immunocompetent, adult patients with P. aeruginosa bacteremia onset at least 2 days after hospital admission between 1 January 2001 and 30 September 2006. Classification and regression tree analysis (CART) was used to identify the delay in appropriate antibiotic therapy that was associated with an increased risk of 30-day mortality. During the study period, 100 patients met the inclusion criteria. The CART-derived breakpoint between early and delayed treatment was 52 h. The delayed treatment group experienced a >2-fold significant increase in 30-day mortality compared to the early treatment group (44 and 19%, respectively, P = 0.008). Delayed appropriate therapy of >52 h (odds ratio [OR] = 4.1; 95% confidence interval [CI] 1.2 to 13.9, P = 0.03) was independently associated with 30-day mortality in the multivariate analysis. Antibiotic resistance ≥3 classes (adjusted OR [AOR] = 4.6; 95% CI = 1.9 to 11.2, P = 0.001) and chronic obstructive pulmonary disease (AOR = 5.4; 95% CI = 1.5 to 19.7, P = 0.01) were independently associated with delayed appropriate therapy of >52 h. The data strongly suggest that delaying appropriate therapy for approximately 2 days significantly increases the risk of 30-day mortality in patients with P. aeruginosa bloodstream infections.

Background Piperacillin-tazobactam is frequently used to treat Pseudomonas aeruginosa infections in critically ill patients. In an effort to improve clinical outcomes, an extended-infusion dosing scheme for piperacillin-tazobactam therapy was devised using a Monte Carlo simulation and was adopted into clinical practice at Albany Medical Center (Albany, New York). This study evaluates the clinical implications of extended infusion of piperacillin-tazobactam therapy for critically ill patients with P. aeruginosa infection. Methods We performed a cohort study of patients who received piperacillin-tazobactam therapy for a P. aeruginosa infection that was susceptible to piperacillin-tazobactam during the period January 2000-June 2004. Prior to February 2002, all patients received intermittent infusions of piperacillin-tazobactam (3.375 g intravenously for 30 min every 4 or 6 h); after this time, all patients received extended infusions of piperacillin-tazobactam (3.375 g intravenously for 4 h every 8 h). Data on demographic characteristics, disease severity, and microbiology were collected, and outcomes were compared between groups. Results A total of 194 patients comprised the 2 study groups: 102 patients received extended infusions of piperacillin-tazobactam, and 92 patients received intermittent infusions of piperacillin-tazobactam. No differences in baseline clinical characteristics were noted between the 2 groups. Among patients with Acute Physiological and Chronic Health Evaluation-II scores > or =17, 14-day mortality rate was significantly lower among patients who received extended-infusion therapy than among patients who received intermittent-infusion therapy (12.2% vs. 31.6%, respectively; P=.04), and median duration of hospital stay after collection of samples for culture was significantly shorter for patients who received extended-infusion therapy than for patients who received intermittent-infusion therapy (21 days vs. 38 days; P=.02).Conclusions. These results indicate that extended-infusion piperacillin-tazobactam therapy is a suitable alternative to intermittent-infusion piperacillin-tazobactam therapy, and they strongly suggest that improved outcomes may be realized by administering extended-infusion piperacillin-tazobactam therapy to critically ill patients with P. aeruginosa infection.

In recent years there have been tremendous strides in understanding the relationship between the pharmacodynamics of beta-lactams and microbiologic response. For beta-lactams, in vitro and animal studies suggest that the amount of time in which free or non-protein-bound antimicrobial concentration exceeds the minimum inhibitory concentration (MIC) of the organism (fT>MIC) is the best predictor of bacterial killing and microbiologic response. Using population pharmacokinetic modeling and Monte Carlo simulation, it is possible to integrate pharmacokinetics, a pharmacodynamic target, and microbiologic surveillance data to generate empiric beta-lactam dosing strategies that maximize the likelihood of achieving fT>MIC associated with near maximal bactericidal effect against the range of pathogens encountered in clinical practice. At Albany Medical Center Hospital, these mathematical modeling techniques were used to devise alternative dosing schemes for piperacillin-tazobactam, meropenem, and cefepime. These alternative schemes optimized fT>MIC at a lower total daily dose than would be employed with traditional dosing methods. Moreover, they achieved the targeted fT>MIC with less administration time/day than would be needed for continuous infusion.

This article focuses on the development of 2 major adverse drug events associated with some fluoroquinolone antimicrobial agents, specifically cardiac and glycemic effects. Cardiac dysfunction, including corrected QT (QTc) interval prolongation and torsades de pointes, has been linked to the administration of fluoroquinolones. The first indication of QTc prolongation was reportedwith sparfloxacin, and since that time, it has been associated with a number of other fluoroquinolones, leading to the assumption that this is a general class effect. Fluoroquinolone-associated effects on cardiac conduction appear more likely to occur in patients with underlying cardiac diseases, those with electrolyte abnormalities, and those coadministered antiarrhythmics and other QTc-prolonging drugs. Some fluoroquinolone agents have also been associated with alterations in glycemic control. Hypoglycemia and hyperglycemia have been reported with many of the currently available agents. Risk factors for aberrations in glucose homeostasis include noninsulindependent diabetes mellitus, increased age, impaired renal function, and the concomitant use of oral hypoglycemic agents. The widespread use of fluoroquinolones highlights the need for clinicians to consider predisposed populations and use caution when selecting antimicrobial therapies.

Objectives. To discuss specific facts regarding use as a bioweapon, epidemiology, microbiology, clinical manifestations, diagnosis, antimicrobial therapy, immunization, and isolation precautions for five most likely agents of bioterrorism; to review and provide recommendations for health care clinicians on the management of these bioterrorism agents; and to share information on the pharmacist's role in preparedness and response. Participants. The manuscript was drafted by the three authors, reviewed by a group of selected members of the Society of Infectious Diseases Pharmacists, and approved by its Board of Directors. Evidence. The primary focus was to review and summarize recent and key articles on bioterrorism. Preference was given to peer-reviewed journal information and government-sponsored journals, such as the MMWR, Morbidity and Mortality Weekly Report. Consensus Process. Written comments were requested from each reviewer. Comments were incorporated into the final draft. Conclusion. Pharmacists play an integral role in disaster preparedness and response and should be involved in planning committees. As drug information specialists, pharmacists can assist other health care providers and emergency personnel, as well as provide counseling to calm, comfort, and empower the public.

Despite advances in antimicrobial chemotherapy over recent decades, morbidity and mortality secondary to infection continues to rise. In addition, the incidence of infection caused by resistant organisms has also increased. Concurrently, the elderly are living longer than prior generations, often with disabling chronic diseases. The more debilitated of the geriatric population are at greater risk for infection, and more likely to acquire or develop antimicrobial resistant organisms. Gram-positive organisms are a source of resistance and commonly cause infection in older patients. Whereas resistance is a concern in all patients, in the elderly this is magnified by limitations in treatment options because of differences in pharmacokinetics and tolerance as compared with younger counterparts. Pharmacokinetic differences include changes in drug distribution and may arise as a result of diminished end organ function. Age-related decreases in renal function often impact on commonly prescribed antimicrobials. In addition, the elderly are more susceptible to drug-drug interactions because polypharmacy is common in this patient population. Streptogramins may offer a useful alternative in the treatment of infections in the elderly due to their coverage of organisms commonly causing infections in this population and because of their favourable pharmacokinetic profiles. While published experience is limited, streptogramins are not appreciably eliminated by the kidney and, therefore, they are less subject to age-related changes in renal elimination. What is required is multi-dose pharmacokinetic analysis of streptogramins in geriatric populations and subset analysis of patient use data on file. The following will provide the reader with the most recently presented data on streptogramin use and their potential. While focusing on potential use in the elderly, we have cited data and issues which we believe will be relevant in the geriatric population.

OBJECTIVE To review recent developments in the pharmacotherapy of obesity, including the agents currently approved for use in the management of obesity and those under development. DATA SOURCES A MEDLINE search from January 1990 to July 1997 was conducted to identify English literature available on the pharmacotherapy of obesity. The search was supplemented by a review of the bibliographies of identified literature. STUDY SELECTION All controlled and uncontrolled trials were reviewed. When available, double-blind, placebo-controlled trials were used preferentially. DATA EXTRACTION Agents were reviewed with regard to mechanism of action, clinical trial data regarding efficacy, adverse effects, pharmacokinetics, drug interactions, and contraindications where information was available. Study design, selected population, results, and adverse effect information were included. DATA SYNTHESIS: The anorexiants currently available or under development for the management of obesity regulate food intake and satiety via the adrenergic and/or serotonergic pathways. Clinical trials have shown a 10–15% weight loss can typically be anticipated; however, little long-term safety and efficacy data are available. Adverse events tend to be mild and self-limiting, but serious adverse events can occur. Treatment options under development include thermogenic agents, digestive inhibitors, and analogs and antagonists of hormones that regulate food intake and satiety. CONCLUSIONS Several mechanisms to control weight are currently under investigation for the management of obesity. Since obesity is a chronic condition, further studies should be conducted to evaluate the long-term safety and efficacy of these agents and the role of combination therapy using different modalities. OBJETIVO Revisar los recientes avances farmacológicos en el tratamiento de la obesidad, incluyendo aquellos medicamentos actualmente aprobados para este uso y otros que todavía se encuentran en desarrollo. FUENTES DE INFORMACION Se realizó una búsqueda computarizada de MEDLINE para determinar artículos publicados en la literatura inglesa entre enero de 1990 a julio de 1997. Además, se utilizarón las referencias citadas en los artículos identificados en la búsqueda. SELECCION DE ESTUDIOS Estudios clínicos de tipo controlados y no-controlados fueron incluidos en el análisis. Se le dió preferencia a aquellos estudios clínicos que eran de diseño doble ciego, controlados, y que usaron un grupo control de placebo. EXTRACCIÓN DE DATOS Los medicamentos fueron evaluados de acuerdo al mecanismo de acción farmacológica, la información ciéntifica relacionada con su eficacia, efectos secundarios, farmacocinética, interacciones de medicamentos, y contraindicaciones de uso. El disefio ciéntifico utilizado en los estudios clínicos, el grupo de pacientes incluido en los estudios, los resultados obtenidos, y los efectos adversos fueron además incluidos en el análisis. SINTESIS Los medicamentos anoréxicos actualmente disponibles para el tratamiento de la obesidad regulan la cantidad de alimentos ingeridos y la sensación de saciedad através de los mecanismos adrenérgicos y de serotonina. Los estudios clínicos disponibles han demostrado que usualmente se puede esperar de un 10–15% de perdida de peso con el uso de estos medicamentos. Sin embargo, no existe mucha información relacionada al uso seguro y la eficacia de estos medicamentos a largo plazo. Los efectos adversos observados con estos medicamentos tienden a ser leves y de corta duración, pero efectos adversos severos pueden ocurrir. Otras opciones de tratamiento incluyen medicamentos termogénicos, inhibidores digestivos, y análogos y antagonistas de diferentes hormonas que regulan la ingestión de alimentos y la sensación de saciedad. CONCLUSIONES Actualmente, algunos de los mecanismos relacionados con el control de peso están siendo investigados para poder determinar futuros tratamientos de la obesidad. Debido a que la obesidad es un problema crónico, se tienen que realizar estudios clínicos adicionales disefiados para evaluar la eficacia y el uso seguro de estos medicamentos a largo plazo. Además, el uso de estos medicamentos en combinación tiene que ser evaluado. OBJECTIF Réviser les développements dans la pharmacothérapie de l'obésité ainsi que les médicaments actuellement utilisés et ceux qui sont en développement. REVUE DE LITTÉRATURE Une recherche sur MEDLINE a été entreprise pour identifier les publications en langue anglaise concernant le traitement de l'obésité et publiées entre janvier 1990 à juillet 1997. Les bibliographies des références pertinentes ont aussi été scrutées. SÉLECTION DES ÉTUDES Toutes les études, contrôlées ou non, ont été révisées. Cependant, les études à double insu ou contrôlées par placebo ont été préférées. EXTRACTION DE L'INFORMATION: Chaque médicament a été révisé pour le mécanisme d'action, les données d'efficacité clinique, les réactions indésirables, la pharmacocinétique, les interactions médicamenteuses, et les contre-indications. Le devis des études, la population à l'étude, les résultats, et les réactions indésirables sont présentes. RÉSUMÉ Les anorexigènes disponibles sur le marché contrôlent l'apport alimentaire et la satiété par une action sur les voies adrénergiques et sérotoninergiques. Les études cliniques ont démontré qu'une perte de poids de 10–15% est un objectif réaliste. Cependant, peu d'études d'efficacité et de sécurité à long terme sont disponibles. Les réactions indésirables sont généralement mineures et se résolvent spontanément. Cependant, des réactions sévères peuvent aussi survenir. De nouvelles avenues thérapeutiques sont en développement. Elles comportent des agents thermogéniques, des inhibiteurs de la digestion, des analogues et antagonistes hormonaux qui régissent l'apport alimentaire et la satiété. CONCLUSIONS Plusieurs stratégies de contrôle de l'obésité sont actuellement en investigation. Puisque l'obésité est une maladie chronique, des études devraient être réalisées pour évaluer l'efficacité et la sécurité des médicaments ainsi que le rôle des thérapies combinées.

A Monte Carlo simulation demonstrated that 1 g of meropenem (MEM) every 8 h (q8h) (3-h infusion) has a higher target attainment rate against Pseudomonas aeruginosa than either 500 mg of MEM q8h (3-h infusion) or 0.5 g of imipenem-cilastatin (I-C) q6h (1-h infusion). For other pathogens, 500 mg of MEM q8h was equivalent or superior to I-C.

Objective: To review the immunogenicity and safety of the Haemophilus influenzae type b- Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine (Hib-MenCY-TT) for infants and toddlers. Data Sources: Studies conducted in humans and limited to publication in English were identified through a MEDLINE (January 2000 to September 2013) search using the terms Hib-MenCY-TT, MenHibrix, and Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine. Clinical trial registries, Web sites, and reference citations from publications identified were reviewed for additional sources. Study Selection and Data Extraction: Randomized controlled trials were included to evaluate the safety and immunogenicity of Hib-MenCY-TT. Epidemiological data and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed. Data Synthesis: Hib-MenCY-TT is available for primary vaccination of infants as a 4-dose series at 2, 4, 6, and 12 to 15 months of age. Hib-MenCY-TT has comparable immunogenicity to licensed Hib vaccines and produces high levels of N meningitidis antibodies against serogroups C and Y. The most common adverse events were pain and redness at the injection site, drowsiness, and irritability. Conclusions: Hib-MenCY-TT has been demonstrated to be a safe and immunogenic vaccination for prevention of disease caused by N meningitidis serogroups C and Y and H influenzae type b in healthy infants and toddlers. Currently, the ACIP recommends the use of Hib-MenCY-TT specifically in high-risk infants aged 6 weeks to 18 months. Hib-MenCY-TT provides the first therapeutic option for vaccination of infants as young as 6 weeks of age who are at increased risk for meningococcal disease.

The purpose of this review is to evaluate the clinical outcomes of drug therapy in the treatment of multiple sclerosis (MS) in those studies which purported to include an assessment of quality of life. Pharmacological management of MS is primarily directed towards control of symptoms and prevention of disease progression or relapse. Although there are many drug and nondrug approaches used in the treatment of MS, this review focuses largely on approaches that incorporate some method of clinical outcome assessment. To aid in the interpretation of the data presented, a short descriptive summary of these assessment methods has been included. Although most studies incorporate at least one clinical outcome measure into the evaluation of efficacy, only one study has examined the economic impact of intervention in MS. The authors of that study demonstrated good correlation between the level of disability assessed using conventional quality-of-life measures and associated healthcare costs. Surprisingly, although many treatment approaches used in MS have significant associated toxicity and only modest benefits in terms of disease control, there is a remarkable paucity of data on the impact of these treatments on patients' quality of life. Studies that incorporate pharmacoeconomic and health-related quality-of-life consequences related to the treatment of MS are required.

Objective: To describe a program of creatinine clearance–based dosage adjustment of 10 renally eliminated antimicrobial agents and to discuss the utility of such a program in a hospital as a method of quality assurance (by ensuring that patients with renal impairment receive generally accepted dosage adjustments), based on pharmacodynamic principles. Methods: Consecutive patients prescribed any of 10 targeted renally eliminated antibiotics were included. Recommendations for dosage adjustment were made to the prescriber based on a calculated creatinine clearance. Additional adjustments in drug therapy were performed, including dosage recommendations of nontargeted drugs, simplification of antibiotic regimens, and conversion of intravenous to oral therapy. A cost analysis was performed. Results: During a 6-month study period, 160 dosage changes (7.6% of total number screened) were recommended in 137 patients receiving the targeted antimicrobial agents. Prescribers accepted 147 recommendations (91.9%). A dosage change recommendation was necessary more than 12% of the time for acyclovir, ceftazidime, and imipenem/cilastatin. A cost avoidance of $11 702.08 was realized. Ancillary drug recommendations that were offered and accepted during the program realized a cost avoidance of $6613.75. Conclusions: This dosage adjustment program using pharmacodynamic principles was successful in optimization of dosing, potential minimization of morbidity caused by excessive dosing, and demonstration of direct and potentially indirect cost avoidance. A dosing program for patients with renal impairment would be of benefit to other clinicians and institutions seeking to optimize patient care.

Objective:To review the current research and importance of glutathione (GSH) therapy in health and disease and to provide a basic overview of the widespread use and interest in this compound.Data Identification:Articles were obtained via a MEDLINE search of the term glutathione in conjunction with specific disease states mentioned, and via extensive review of references found in articles identified by computer search.Study Selection:Emphasis was placed on the most recent research, human research, and in discussing multiple disease states.Data Extraction:The literature was reviewed for methodology, quality, and practical aspects of interest to clinical pharmacists.Data Synthesis:GSH is a tripeptide of extreme importance as a catalyst, reductant, and reactant. It continues to be investigated in diverse areas such as acute respiratory distress syndrome, toxicology, AIDS, aging, oncology, and liver disease. Despite the widespread clinical interest in GSH, we were not able to identify an in-depth review of this compound in the pharmacy literature.Conclusions:The list of potential indications for modulation of GSH is extensive and broad. This review introduces clinicians to what GSH is, its basic chemistry, and some areas of active research.

While extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50% f T>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50% f T>MIC for MICs of ≥8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximize f T>MIC in certain hospitalized populations.

We sought to characterize the pharmacodynamic profile of the more intensive vancomycin dosing regimens currently used in response to the recent vancomycin guidelines.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.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.This study indicates that vancomycin may not be useful for treating serious methicillin-resistant Staphylococcus aureus (MRSA) infections with MIC values1 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.

Vancomycin is a commonly used antibiotic due to its effectiveness in treating serious gram-positive infections caused by methicillin-resistant Staphylococcus aureus. As commercial drug assays and a multitude of pharmacokinetic data from a variety of patient populations are widely available, therapeutic monitoring of serum vancomycin concentrations is frequently performed by clinicians, with the expectation that targeting the concentrations within a relatively narrow range can minimize toxicity yet still achieve therapeutic success. Much debate exists, however, over the value of routine therapeutic monitoring of vancomycin levels because of conflicting evidence regarding the ability of serum concentrations to predict effectiveness or prevent toxicity. In addition, studies have suggested that the potential for nephrotoxicity or ototoxicity with vancomycin monotherapy is minimal at conventional dosages of 1 g (15 mg/kg) every 12 hours. However, increased rates of nephrotoxicity have recently been reported with doses of 4 g/day or higher. The American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists published a consensus statement on therapeutic monitoring of serum vancomycin levels in adults. These organizations established an expert panel to review the scientific data and controversies associated with vancomycin monitoring and to make recommendations based on the available evidence. As the members of this panel, we summarize the conclusions and highlight the recommendations from the consensus statement. We determined that the area under the concentration-time curve (AUC): minimum inhibitory concentration (MIC) ratio is the most useful pharmacodynamic parameter to predict vancomycin effectiveness and suggested a target ratio of 400 or greater to eradicate S. aureus. In addition, trough serum concentration monitoring is the most accurate and practical method to monitor vancomycin serum levels. Increasing trough concentrations to 15-20 mg/L to attain the target AUC:MIC ratio may be desirable but is currently not supported by clinical trials. Alternative therapies should be considered in patients with S. aureus infections that demonstrate a vancomycin MIC of 2 mg/L or greater because the target AUC:MIC ratio ( 400) is unlikely to be achieved in this setting. Increasing the dosage to result in higher trough concentrations may increase the potential for toxicity; however additional clinical experience is required to determine the extent.

Practice guidelines for therapeutic monitoring of vancomycin treatment for Staphylococcus aureus infection in adult patients were reviewed by an expert panel of the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. A literature review of existing evidence regarding vancomycin dosing and monitoring of serum concentrations, in addition to patient outcomes combined with expert opinion regarding the drug's pharmacokinetic, pharmacodynamic, and safety record, resulted in new recommendations for targeting and adjustment of vancomycin therapy.

The quinolone class of antibiotics is enjoying a recent resurgence in interest and use due to the development of improved compounds. Norfloxacin, ciprofloxacin, and, most recently, ofloxacin have been marketed. Enoxacin and other agents are in various stages of investigation. These newer compounds are often used for indications not successfully treated by the original quinolones, or in some cases, not optimally treated with any previously available oral antibiotic. A potential problem with the increasing use of quinolone-type antibiotics for systemic illness is the chelation and inactivation of these compounds by several cations. One outcome of these potential interactions is a possible reduction in bioavailability and effectiveness of quinolone compounds. A review of the literature on quinolone-cation interactions, in vivo and in vitro significance, and recommendations to avoid potential problems are provided.

The effect on ciprofloxacin's bioavailability (F) of calcium carbonate given 2 h before ciprofloxacin administration in 12 male volunteers was studied. The relative F with calcium was 0.98, maximum concentration of drug in serum increased significantly from 1.98 to 2.42 mg/liter (P = 0.039), and time to maximum concentration of drug in serum decreased from 1.82 to 1.26 h (P = 0.038). Thus, a single calcium carbonate dose, administered 2 h before ciprofloxacin, does not alter the F of this quinolone.

Despite the increasing prevalence of multiple-drug-resistant (MDR) Pseudomonas aeruginosa , the factors predictive of MDR have not been extensively explored. We sought to examine factors predictive of MDR among patients with P. aeruginosa respiratory tract infections and to develop a tool to estimate the probability of MDR among such high-risk patients. This was a single-site, case-control study of patients with P. aeruginosa respiratory tract infections. Multiple-drug resistance was defined as resistance to four or more antipseudomonal antimicrobial classes. Clinical data on demographics, antibiotic history, and microbiology were collected. Classification and regression tree analysis (CART) was used to identify the duration of antibiotic exposure associated with MDR P. aeruginosa . Log-binomial regression was used to model the probability of MDR P. aeruginosa . Among 351 P. aeruginosa -infected patients, the proportion of MDR P. aeruginosa was 35%. A significant relationship between prior antibiotic exposure and MDR P. aeruginosa was found for all of the antipseudomonal antibiotics studied, but the duration of prior exposure associated with MDR varied between antibiotic classes; the shortest prior exposure duration was observed for carbapenems and fluoroquinolones, and the longest duration was noted for cefepime and piperacillin-tazobactam. Within the final model, the predicted MDR P. aeruginosa likelihood was most dependent upon length of hospital stay, prior culture sample collection, and number of CART-derived prior antibiotic exposures. A history of a prolonged hospital stay and exposure to antipseudomonal antibiotics predicts multidrug resistance among patients with P. aeruginosa respiratory tract infections at our institution. Identifying these risk factors enabled us to develop a prediction tool to assess the risk of resistance and thus guide empirical antibiotic therapy.

Klebsiella pneumoniae carbapenemases (KPCs) have previously been identified in distinct geographic locations. We report the spread of KPC-2 to upstate New York. Our intention is to alert clinicians to problems encountered in identifying KPC-containing isolates. Possible errors as a result of inferring susceptibility of untested carbapenems from the routine antibiogram using agar-based methodology or microdilution testing are discussed.

The primary objectives of this analysis were to determine which pharmacokinetic model most accurately describes the elimination pathways for piperacillin in the presence of tazobactam through population pharmacokinetic modeling and to characterize its pharmacodynamic profile. Once the optimal pharmacokinetic model was identified, Monte Carlo simulation of 10,000 subjects with ADAPT II was performed to estimate the probability of attaining a target free-piperacillin concentration greater than the MIC for 50% of the dosing interval for 3.375 g every 6 h or every 4 h given as a 0.5-h infusion at each MIC between 0.25 and 32 μg/ml. In the population pharmacokinetic analysis, measurements of bias and precision, observed-predicted plots, and r 2 values were highly acceptable for all three models and all three models were appropriate candidates for the Monte Carlo simulation evaluation. Visual comparison of the distribution of the piperacillin concentrations at the pharmacodynamic endpoint—h 3 concentrations of a 6-h dosing interval—between the simulated populations and raw data revealed that the linear model was most reflective of the raw data at the pharmacodynamic endpoint, and the linear model was therefore selected for the target attainment analysis. In the target attainment analysis, administration of 3 g of piperacillin every 6 h resulted in a robust target attainment rate that exceeded 95% for MICs of ≤8 mg/liter. The 4-h piperacillin administration interval had a superior pharmacodynamic profile and provided target attainment rates exceeding 95% for MICs of ≤16 mg/liter. This study indicates that piperacillin-tazobactam should have utility for empirical therapy of hospital-onset infections.

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. Patients. One thousand patients with creatinine clearances of 120, 90, or 60 ml/minute. Intervention. Administration of a standard dosage of cefepime 2 g every 12 hours, each dose infused over 0.5 hour, and maximum dosage of 2 g every 8 hours, each dose infused over 0.5 hour; and a nonstandard dosage of 2 g every 12 hours, each dose infused over 6 hours, and continuous infusion of 4 g infused over 24 hours. Measurements and Main Results. The standard and maximum dosages achieved pharmacodynamic targets from 4–38% and 21–68%, respectively for the three groups. With extended infusion of the standard dosage, the probability of achieving the pharmacodynamic target increased to 18–63%. Continuous infusion over 24 hours offered the most promising pharmacodynamic target, attaining 65–81% (p

Fluoroquinolones are generally well tolerated, clinically useful antimicrobials. This paper highlights rare, but potentially serious, adverse effects involving the kidney. Other antimicrobials have long been known to cause various forms of nephrotoxicity occurring as allergic interstitial nephritis, granulomatous interstitial nephritis, necrotising vasculitis, allergic tubular nephritis or a tubular necrosis. A Medline search (1985 to May 1999) of ciprofloxacin, norfloxacin, levofloxacin, ofloxacin, trovafloxacin, enoxacin, sparfloxacin, grepafloxacin, gatifloxacin, clinafloxacin and moxifloxacin was conducted to ascertain the incidence and features of fluoroquinolone nephrotoxicity. Unfortunately, the data primarily consist of case reports and temporally related events. The incidence of these adverse effects is hard to estimate, and the cause may be multifactorial. While the use of ciprofloxacin appears to increase the risk, this may be due to its longer and more widespread use when compared with the newer agents.

OBJECTIVE: T o review and update the incidence, mechanism, and clinical relevance of drug interactions with itraconazole, ketoconazole, and fluconazole. DATA SOURCES: Literature was identified by MEDLINE search (from January 1990 to May 1997) using the name of each antifungal and the term “interaction” as MeSH headings. Abstracts were identified by literature citation and by review of Interscience Conference on Antimicrobial Agents and Chemotherapy from 1995 to 1996. STUDY SELECTION: Randomized, controlled, double-blind studies were emphasized; however, uncontrolled studies and case reports were also included. In vitro data were selected from literature review and citations. DATA EXTRACTION: Data were evaluated with respect to study design, clinical relevance, magnitude of interaction, and recommendations provided. DATA SYNTHESIS: The incidence of fungal infections and consequent azole antifungal usage continues to increase. By virtue of their antifungal mechanism (i.e., inhibition of cytochrome P450 fungal enzyme systems), azoles have been investigated and implicated in several drug interactions. The magnitude of interactions can vary from trivial to potentially fatal, and also vary with specific azole and interactant. CONCLUSIONS: The azole antifungal agents represent a commonly used class of agents with a broad range of potential interactions. Recent data have increased our understanding of drug-drug interactions with azoles. Pharmacists are in a unique position to identify these interactions and to intervene to decrease their morbidity and improve patient care.

The utility of the fluoroquinolone class of antibiotics is rapidly expanding due to their favourable pharmacokinetic profile and the continuing development of new compounds. These agents are often used for indications not successfully treated with other orally available antimicrobials in the past, or for ‘step-down’ therapy in patients originally treated with intravenous agents. As the usage of these agents expands for serious systemic infections, knowledge of absorptive interactions with fluoroquinolones becomes paramount. Fluoroquinolones are often utilised in dosages and against modestly susceptible pathogens which allow a narrow margin for acceptable decreases in bioavailability. Chelation interactions with multivalent cations can result in inactivation of the fluoroquinolone with ramifications in vitro and in vivo. Chelation interactions have been reported to occur in between 22 and 76% of patients prescribed fluoroquinolones. Concurrent administration of magnesium-aluminium antacids and sucralfate has the greatest effect on the bioavailability of quinolones followed by iron, calcium and zinc. Spacing doses of fluoroquinolones and interactants has been suggested as a method of ensuring adequate quinolone absorption, but this can make optimal administration of the cation interactant difficult, if not imposible.

OBJECTIVE: To determine the effect on the relative bioavailability (Fr) of a staggered single dose of ciprofloxacin given two hours after a morning dose of calcium carbonate given three times daily over the three previous days. DESIGN: Thirteen male volunteers participated in this randomized, nonblinded, crossover investigation; 12 subjects were included in the final analysis. SETTING: Data collection and ciprofloxacin administration occurred at Albany Medical Center, a tertiary-care teaching institution. Calcium carbonate administration was on an outpatient basis. RESULTS: For 12 volunteers, the mean ± SD Fr of ciprofloxacin staggered with calcium was 0.87 ± 0.23 (noncompartmental model) and 0.98 ± 0.27 (compartmental model). Other statistically significant findings were a decrease in the time to maximum concentration of ciprofloxacin staggered with calcium in serum compared with ciprofloxacin alone (from 1.76 ± 0.54 to 1.23 ± 0.52 h in the noncompartmental model; pCONCLUSIONS: Repeated doses of calcium carbonate, administered two hours before ciprofloxacin, did not significantly alter the Fr of this fluoroquinolone.

Background: Improved understanding of medication-prescribing errors should be useful in the design of error prevention strategies. Objective: To report analysis of a 9-year experience with a systematic program of detecting, recording, and evaluating medication-prescribing errors in a teaching hospital. Methods: All medication-prescribing errors with potential for adverse patient outcome detected and averted by staff pharmacists from January 1, 1987, through December 31, 1995, were systematically recorded and analyzed. Errors were evaluated by type of error, medication class involved, prescribing service, potential severity, time of day, and month. Data were analyzed to determine changes in medication-prescribing error frequency and characteristics occurring during the 9-year study period. Results: A total of 11 186 confirmed medication-prescribing errors with potential for adverse patient consequences were detected and averted during the study period. The annual number of errors detected increased from 522 in the index year 1987 to 2115 in 1995. The rate of errors occurring per order written, per admission, and per patient-day, all increased significantly during the study duration (P Conclusions: The results of this study suggest there may exist a progressively increasing risk of adverse drug events for hospitalized patients. The increased rate of errors is possibly associated with increases in the intensity of medical care and use of drug therapy. Limited changes in the characteristics of prescribing errors occurred, as similar type errors were found to be repeated with increasing frequency. New errors were encountered as new drug therapies were introduced. Health care practitioners and health care systems must incorporate adequate error reduction, prevention, and detection mechanisms into the routine provision of care. Arch Intern Med. 1997;157:1569-1576

To the Editor: In September 1993 we reported on the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, which involved 41,021 patients with acute myocardial infarction (Sept. 2 issue).1 In that report, we erred in stating that there was a 99.9 percent level of completeness of “30-day mortality outcomes”; this should have read “in-hospital outcomes.” Since our initial report, we have received complete data on outcomes at 30 days in all but 98 patients (0.2 percent) and there has been refinement in the data base for variables for which either data were missing or . . .