Evaluation of the timing of MRSA PCR nasal screening: How long can a negative assay be used to rule out MRSA-positive respiratory cultures?

PURPOSE: Previous studies indicate that the polymerase chain reaction (PCR) nasal assay for methicillin-resistant Staphylococcus aureus (MRSA) has a consistently high (>95%) negative predictive value (NPV) in ruling out MRSA pneumonia; however, optimal timing of PCR assay specimen and respiratory culture collection is unclear. METHODS: A study including 736 patients from a community hospital system was conducted. Patients were included if they had undergone MRSA nasal screening with a PCR assay and had documented positive respiratory culture results. RESULTS: In the full cohort, the MRSA PCR nasal screen assay was demonstrated to have an NPV of 94.9% (95% confidence interval [CI], 92.8%-96.5%) in ruling out MRSA-positive respiratory cultures. When evaluating the NPV by level of care (ie, where the MRSA PCR nasal assay sample was collected), no significant difference between values for samples collected in an intensive care unit vs medical/surgical units was identified (NPV [95%CI], 94.9% [92.7%-96.6%] vs 95.3% [88.4%-98.7%]). Additionally, NPV remained high with use of both invasive (NPV [95%CI], 96.8% [92.7%-99.0%]) and noninvasive (NPV [95%CI], 94.5% [91.7%-96.2%]) respiratory sampling methods. Finally, when evaluating the effect of time between MRSA PCR nasal screening and respiratory sample collection, we found high NPVs for all evaluated timeframes: within 24 hours, 93.8% (90.1%-96.4%); within 25 to 48 hours, 98.6% (92.7%-100.0%); within 49 hours to 7 days, 95.7% (91.4%-98.3%); within 8 to 14 days, 92.9% (85.1%-97.3%); and after more than 14 days, 95.5% (84.5%-99.4%). CONCLUSION: We report high NPVs for up to 2 weeks between specimen collections, which allows clinicians to use a negative MRSA PCR nasal screen assay to rule out MRSA pneumonia, potentially leading to decreased exposure to MRSA-active antibiotics.

Antibiotic utilization within 18 community hospitals in the United States: A 5-year analysis.

BACKGROUND: Antibiotic overuse is associated with antibiotic resistance. We evaluated antibiotic utilization defined by days of therapy/1000 patient days (DOT/1000 PD) in various community hospitals across the United States. METHODS: Community hospitals within the Cardinal Health Drug Cost Opportunity Analytics database were evaluated for the availability of DOT/1000 PD data between 2012 to 2016 for overall and specific antibiotic use and the following classes: narrow-spectrum ß-lactams (ampicillin, nafcillin, oxacillin, cefazolin, and cephalexin), non-carbapenem antipseudomonal ß-lactams (piperacillin/tazobactam, ceftazidime, and cefepime), carbapenems, anti-methicillin-resistant Staphylococcus aureus agents (vancomycin, linezolid, daptomycin, and tigecycline), and fluoroquinolones. Antibiotic utilization and change in utilization during the study period was calculated using linear regression (ß coefficient). RESULTS: Eighteen hospitals had antibiotic utilization data available. Hospitals were primarily urban (72%) with an average of 209 total beds and 22 intensive care unit beds. Mean number of pharmacists in these hospitals was nine with a mean pharmacist: bed ratio of 0.05. While all hospitals had antimicrobial stewardship programs established during the study period, only 78% and 22% had infectious diseases (ID) physician and ID pharmacist on staff, respectively. A decrease in antipseudomonal ß-lactams (excluding carbapenems) and fluoroquinolones was observed (ß coefficients = -1.2 and -2.6, respectively), all other antibiotic classes had increased utilization. CONCLUSION: Overall antibiotic utilization increased over 5 years. The increase in narrow-spectrum ß-lactams utilization along with the reduction in the use of antipseudomonal ß-lactams and fluoroquinolones indicate appropriate antimicrobial stewardship. Institutional antibiotic utilization should be evaluated for appropriateness to limit the overuse of broad-spectrum antibiotics in an effort to reduce resistance development.

Global climate change and health in Canadian children.

Climate change is a reality. Numerous expert authorities warn of the critical need to undertake and adapt environmental efforts to protect human health. Climate change is accelerating, and countries in high latitudes, such as Canada, are experiencing climate change more directly and, for some end points, more dramatically than mid- and low-latitude countries. Children are vulnerable to climate change health effects, and physicians and other health care providers need to be ready to identify, manage, and prevent climate change-related health hazards. This practice point highlights specific, climate change-related threats to the health of children and youth, and provides resources for health care providers. Climate challenges and their health impacts on children are described, based on key Canadian reports and scientifically referenced information. Enhanced awareness of the immediate and longer-term health effects of climate change on children allows physicians and other health care providers to counsel families and practice more effectively.

The Pharmacodynamics of Prolonged Infusion ß-Lactams for the Treatment of Pseudomonas aeruginosa Infections: A Systematic Review.

PURPOSE: Pseudomonas aeruginosa is a commonly isolated nosocomial pathogen for which treatment options are often limited for multidrug-resistant isolates. In addition to newer available antimicrobial agents active against P. aeruginosa, strategies such as extended (eg, prolonged or continuous) infusion have been suggested to optimize the pharmacokinetic and pharmacodynamic profiles of ß-lactams. Literature regarding clinical outcomes for extended infusion ß-lactams has been controversial; however, this use seems most beneficial in patients with severe illness. Prolonged infusion of ß-lactams (eg, 3- to 4-hour infusion) can enhance the pharmacodynamic target attainment via increasing the amount of time throughout the dosing interval to which the free drug concentration remains above the MIC (minimum inhibitory concentration) of the organism (fT > MIC). This systematic review summarizes current literature related to the probability of target attainment (PTA) of various antipseudomonal ß-lactam regimens administered as prolonged infusions in an effort to provide guidance in selecting optimal dosing regimens and infusion times for the treatment of P. aeruginosa infections. METHODS: A literature search for all pertinent studies was performed by using the PubMed database (with no year limit) through March 31, 2019. FINDINGS: Thirty-nine studies were included. Although many standard antipseudomonal ß-lactam intermittent infusion regimens can provide adequate PTA against most susceptible isolates, prolonged infusion may enhance percent fT > MIC for organisms with higher MICs (eg, nonsusceptible) or patients with altered pharmacokinetic profiles (eg, obese, critically ill, those with febrile neutropenia). IMPLICATIONS: Prolonged infusion ß-lactam regimens can enhance PTA against nonsusceptible P. aeruginosa isolates and may provide a potential therapeutic option for multidrug-resistant infections. Before implementing prolonged infusion antipseudomonal ß-lactams, institutions should consider the half-life of the antibiotic, local incidence of P. aeruginosa infections, antibiotic MIC distributions or MICs isolated from individual patients, individual patient characteristics that may alter pharmacokinetic variables, and PTA (eg, critically ill), as well as implementation challenges.

Electronic Medical Record Reporting Enhances Proactive Psychiatric Consultation.

BACKGROUND: Numerous studies have demonstrated that psychiatric and substance use issues in general hospital inpatients result in increased length of stay and associated costs. Additional studies have demonstrated that proactive consultation models in psychiatry can effectively address these problems. Selecting patients for proactive interventions is less well studied. OBJECTIVE: We sought to develop an automated, electronic medical record-based screening tool to select patients who might benefit from proactive psychiatric consultation. METHODS: An automated daily report was developed using information stored in electronic medical record and billing systems. Discrete data fields populating the report included diagnoses, orders, and nursing care plans. RESULTS: Over a 9-month period, the report identified 2177 patients (19% of the total nonpsychiatric adult admissions) as potentially benefitting from proactive psychiatric interventions. Of these, 367 were confirmed as likely to benefit from intervention; 139 (38%) were randomized to the proactive psychiatric consultation group. Of those patients randomized to "treatment as usual," a subset later required psychiatric consultation, which was requested an average of 4 days after the time they were flagged by the report. CONCLUSIONS: The use of an electronic medical record-based automated report is feasible to select patients for proactive psychiatric interventions on admission and throughout the hospital stay. Early identification of patients may decrease length of stay and improve patient outcomes.

Impact of an antiretroviral stewardship strategy on medication error rates.

PURPOSE: The impact of an antiretroviral stewardship strategy on medication error rates was evaluated. METHODS: This single-center, retrospective, comparative cohort study included patients at least 18 years of age infected with human immunodeficiency virus (HIV) who were receiving antiretrovirals and admitted to the hospital. A multicomponent approach was developed and implemented and included modifications to the order-entry and verification system, pharmacist education, and a pharmacist-led antiretroviral therapy checklist. Pharmacists performed prospective audits using the checklist at the time of order verification. To assess the impact of the intervention, a retrospective review was performed before and after implementation to assess antiretroviral errors. RESULTS: Totals of 208 and 24 errors were identified before and after the intervention, respectively, resulting in a significant reduction in the overall error rate (p < 0.001). In the postintervention group, significantly lower medication error rates were found in both patient admissions containing at least 1 medication error (p < 0.001) and those with 2 or more errors (p < 0.001). Significant reductions were also identified in each error type, including incorrect/incomplete medication regimen, incorrect dosing regimen, incorrect renal dose adjustment, incorrect administration, and the presence of a major drug-drug interaction. A regression tree selected ritonavir as the only specific medication that best predicted more errors preintervention (p < 0.001); however, no antiretrovirals reliably predicted errors postintervention. CONCLUSION: An antiretroviral stewardship strategy for hospitalized HIV patients including prospective audit by staff pharmacists through use of an antiretroviral medication therapy checklist at the time of order verification decreased error rates.

Significant Publications on Infectious Diseases Pharmacotherapy in 2016.

PURPOSE: This is a summary of the most important articles on infectious diseases (ID) pharmacotherapy published in peer-reviewed literature in 2016 as selected by clinical pharmacists with ID expertise. SUMMARY: The Houston Infectious Diseases Network (HIDN) was asked to identify articles published in peer-reviewed literature in 2016 that were believed to contribute significantly to ID pharmacotherapy, including human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). A list of 46 articles on general ID pharmacotherapy and 8 articles on HIV/AIDS were nominated. Members of the Society of Infectious Diseases Pharmacists (SIDP) were surveyed to select 10 general ID articles believed to have made a significant impact on general ID pharmacotherapy and 1 article most significant to HIV/AIDS pharmacotherapy. Of 445 SIDP members surveyed, 212 (47.6%) and 95 (21.3%) members voted for general ID pharmacotherapy- and HIV/AIDS-related articles, respectively. The 11 highest-ranked papers (10 general ID-related articles and 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the large number of ID-related articles published each year, it can be challenging to stay current with the most relevant ID publications. This review of significant publications in 2016 may provide a starting point for that process.

Correction: Hydration Status as a Predictor of High-altitude Mountaineering Performance.

[This corrects the article DOI: 10.7759/cureus.918.].

Effect of a Health Care System Respiratory Fluoroquinolone Restriction Program To Alter Utilization and Impact Rates of Clostridium difficile Infection.

Fluoroquinolones are one of the most commonly prescribed antibiotic classes in the United States despite their association with adverse consequences, including Clostridium difficile infection (CDI). We sought to evaluate the impact of a health care system antimicrobial stewardship-initiated respiratory fluoroquinolone restriction program on utilization, appropriateness of quinolone-based therapy based on institutional guidelines, and CDI rates. After implementation, respiratory fluoroquinolone utilization decreased from a monthly mean and standard deviation (SD) of 41.0 (SD = 4.4) days of therapy (DOT) per 1,000 patient days (PD) preintervention to 21.5 (SD = 6.4) DOT/1,000 PD and 4.8 (SD = 3.6) DOT/1,000 PD posteducation and postrestriction, respectively. Using segmented regression analysis, both education (14.5 DOT/1,000 PD per month decrease; P = 0.023) and restriction (24.5 DOT/1,000 PD per month decrease; P < 0.0001) were associated with decreased utilization. In addition, the CDI rates decreased significantly (P = 0.044) from preintervention using education (3.43 cases/10,000 PD) and restriction (2.2 cases/10,000 PD). Mean monthly CDI cases/10,000 PD decreased from 4.0 (SD = 2.1) preintervention to 2.2 (SD = 1.35) postrestriction. A significant increase in appropriate respiratory fluoroquinolone use occurred postrestriction versus preintervention in patients administered at least one dose (74/130 [57%] versus 74/232 [32%]; P < 0.001), as well as in those receiving two or more doses (47/65 [72%] versus 67/191 [35%]; P < 0.001). A significant reduction in the annual acquisition cost of moxifloxacin, the formulary respiratory fluoroquinolone, was observed postrestriction compared to preintervention within the health care system ($123,882 versus $12,273; P = 0.002). Implementation of a stewardship-initiated respiratory fluoroquinolone restriction program can increase appropriate use while reducing overall utilization, acquisition cost, and CDI rates within a health care system.

Correction: Hydration Status as a Predictor of High-altitude Mountaineering Performance.

[This corrects the article DOI: 10.7759/cureus.918.].

Operational and Clinical Strategies to Address Drug Cost Containment in the Acute Care Setting.

OBJECTIVE: To provide clinical and operational strategies to generate drug cost savings in the hospital setting. METHODS: A search of the PubMed database was performed with no time limit through July 2016. All original prospective and retrospective studies, peer-reviewed guidelines, consensus statements, review articles, and accompanying references were evaluated for inclusion. Only articles published in the English language were included. MAIN RESULTS: Investigators reviewed 937 abstracts. The review of the literature showed that acute care hospitals are under increasing financial pressures, and the pharmacy is often responsible for opportunities to manage drug costs. The literature also indicated that cost-containment strategies in the acute care setting range from pharmacy-directed activities to initiatives requiring interdisciplinary collaboration and strategic planning. Hospital pharmacies should consider establishing an interdisciplinary team that is responsible for systematically reviewing drug cost implications and leading any initiatives that are deemed necessary. Acute care settings can use various operational and clinical strategies to lower their expenditures on high-cost drugs. Operational strategies include various activities that pharmacy staff implement related to contracting, purchasing, and inventory management. Clinical strategies utilize clinical pharmacists working with interdisciplinary teams to develop and maintain a formulary, implement established-use criteria for select drugs, use dose optimization, and implement other clinical tactics aimed at cost containment. After initiatives are implemented, assessing the outcomes of the initiatives is important to determine how successful they were at lowering costs safely and effectively. CONCLUSION: Acute care hospitals can use various operational and clinical strategies to lower overall drug costs. A systematic stepwise approach is recommended to ensure relevant drugs are regularly reviewed and addressed as needed.

Are first-generation cephalosporins obsolete? A retrospective, non-inferiority, cohort study comparing empirical therapy with cefazolin versus ceftriaxone for acute pyelonephritis in hospitalized patients.

OBJECTIVES: Literature is lacking regarding the utilization of first-generation cephalosporins for the treatment of acute pyelonephritis. The aim of this study was to determine whether cefazolin is non-inferior to ceftriaxone for the empirical treatment of acute pyelonephritis in hospitalized patients. The primary outcome included a composite of symptomatic resolution plus either defervescence at 72 h or normalization of serum white blood cell count at 72 h (non-inferiority margin 15%). Secondary outcomes included length of stay and 30 day readmission. A subgroup analysis of the composite outcome was also conducted for imaging-confirmed pyelonephritis. METHODS: This was a retrospective, non-inferiority, multicentre, cohort study comparing cefazolin versus ceftriaxone for the empirical treatment of acute pyelonephritis in hospitalized patients. RESULTS: Overall, 184 patients received one of the two treatments between July 2009 and March 2015. The composite outcome was achieved in 80/92 (87.0%) in the cefazolin group versus 79/92 (85.9%) in the ceftriaxone group (absolute difference 1.1%, 95% CI -11.1% to 8.9%, P = 0.83), meeting the pre-defined criteria for non-inferiority. The composite outcome for patients with imaging-confirmed pyelonephritis was achieved in 46/56 (82.1%) versus 42/50 (84.0%) for the cefazolin group and the ceftriaxone group, respectively (absolute difference 1.9%, 95% CI -12.8% to 16.5%, P = 0.80). Additionally, there were no statistically significant differences in length of stay or 30 day readmission for cystitis or pyelonephritis. CONCLUSIONS: Cefazolin was non-inferior to ceftriaxone with regard to clinical response for the treatment of hospitalized patients with acute pyelonephritis in this study. No difference was observed for length of stay or 30 day readmission.

The 6-Minute Walk Test as a Predictor of Summit Success on Denali.

OBJECTIVE: To test whether the 6-minute walk test (6MWT), including postexercise vital sign measurements and distance walked, predicts summit success on Denali, AK. METHODS: This was a prospective observational study of healthy volunteers between the ages of 18 and 65 years who had been at 4267 m for less than 24 hours on Denali. Physiologic measurements were made after the 6MWT. Subjects then attempted to summit at their own pace and, at the time of descent, completed a Lake Louise Acute Mountain Sickness Questionnaire and reported maximum elevation reached. RESULTS: One hundred twenty-one participants enrolled in the study. Data were collected on 111 subjects (92% response rate), of whom 60% summited. On univariate analysis, there was no association between any postexercise vital sign and summit success. Specifically, there was no significant difference in the mean postexercise peripheral oxygen saturation (Spo2) between summiters (75%) and nonsummiters (74%; 95% CI, -3 to 1; P = .37). The distance a subject walked in 6 minutes (6MWTD) was longer in summiters (617 m) compared with nonsummiters (560 m; 95% CI, 7.6 to 106; P = .02). However, this significance was not maintained on a multivariate analysis performed to control for age, sex, and guide status (P = .08), leading to the conclusion that 6MWTD was not a robust predictor of summit success. CONCLUSIONS: This study did not show a correlation between postexercise oxygen saturation or 6MWTD and summit success on Denali.

Hydration Status as a Predictor of High-altitude Mountaineering Performance.

BACKGROUND: Hydration status is a controversial determinant of athletic performance. This relationship has not been examined with mountaineering performance. METHODS: This was a prospective observational study of mountaineers who attempted to climb Denali in Alaska. Participants' urine specific gravity (SG), and ultrasound measurements of the inferior vena cava size and collapsibility index (IVC-CI) were measured at rest prior to ascent. Upon descent, climbers reported maximum elevation gained for determination of summit success. RESULTS: One hundred twenty-one participants enrolled in the study. Data were collected on 111 participants (92% response rate); of those, 105 (87%) had complete hydration data. Fifty-seven percent of study participants were found to be dehydrated by IVC-CI on ultrasound, and 55% by urine SG. No significant association was found with summit success and quantitative measurements of hydration: IVC-CI (50.4% +/- 15.6 vs. 52.9% +/- 15.4, p = 0.91), IVC size (0.96 cm +/- 0.3 vs. 0.99 cm +/- 0.3, p = 0.81), and average SG (1.02 +/- 0.008 vs. 1.02 +/- 0.008, p = 0.87). Categorical measurements of urine SG found 24% more successful summiters were hydrated at 14 Camp, but this was not found to be statistically significant (p = 0.56). Summit success was associated with greater water-carrying capacity on univariate analysis only: 2.3 L, 95% confidence interval (2.1 - 2.5) vs. 2.1 L, 95% confidence interval (2 - 2.2); p < 0.01. CONCLUSIONS: Intravascular dehydration was found in approximately half of technical high-altitude mountaineers. Hydration status was not significantly associated with summit success, but increased water-carrying capacity may be an easy and inexpensive educational intervention to improve performance.

Incidence and Prevalence of Acute Kidney Injury During Multistage Ultramarathons.

OBJECTIVE: Determine prevalence, incidence, and risk factors of acute kidney injury (AKI) during multistage ultramarathons. DESIGN: Prospective observational cohort study. SETTING: Jordanian Desert 2012; Atacama Desert, Chile 2012 and 2013; and Gobi Desert 2013 RacingThePlanet 250 km, 6-stage, ultramarathons. PARTICIPANTS: One hundred twenty-eight participants (384 measurements) from the Jordan (25, 19.5%), Gobi (35, 27.3%), 2012 Atacama (24, 18.8%), and 2013 Atacama (44, 34.4%) races. INTERVENTIONS: Blood samples and weights were gathered and analyzed immediately after stage 1 (40 km), 3 (120 km), and 5 (225 km). MAIN OUTCOME MEASURES: Changes in serum creatinine (Cr), cumulative incidence, and prevalence of AKI were calculated for each stage with "risk of injury" defined as 1.5 × baseline Cr and "injury" defined as 2 × Cr. RESULTS: Cumulative incidence of AKI was 41.4%. Stage 1 had 56 (43.8%) with risk of AKI and 24 (18.8%) with injury; in stage 3, 61 (47.7%) were at risk, 41 (32%) had injury; in stage 5, 62 (48.4%) runners were at risk and 36 (28.1%) had injury. Acute kidney injury was significantly associated with females [odds ratio (OR), 4.64; 95% confidence interval (CI), 2.07-10.37; P < 0.001], lower pack weight (OR, 0.71; 95% CI, 0.56-0.91; P < 0.007), and percentage weight loss (OR, 0.87; 95% CI, 0.78-0.97; P < 0.015). Lowest quintile of finishers was less likely to develop AKI (OR, 0.18; 95% CI, 0.04-0.78; P < 0.022). CONCLUSIONS: Prevalence of AKI was 63%-78% during multistage ultramarathons. Female sex, lower pack weight, and greater weight loss were associated with renal impairment.

Implications of Augmented Renal Clearance on Drug Dosing in Critically Ill Patients: A Focus on Antibiotics.

Augmented renal clearance (ARC) has been reported in approximately 30-65% of patients in the intensive care unit (ICU) despite the presence of a normal serum creatinine concentration. In certain ICU patient populations (e.g., patients with sepsis or trauma), the incidence increases to roughly 50-85%. Risk factors for ARC include the following: age younger than 50-55 years, male sex, higher diastolic blood pressure, fewer comorbidities, and a lower Acute Physiology and Chronic Health Evaluation II (APACHE II) or modified Sequential Organ Failure Assessment (SOFA) score at ICU admission. In addition, patient populations with the highest reported incidence of ARC include those with major trauma, sepsis, traumatic brain injury, subarachnoid hemorrhage, and central nervous system infection. Due to the high incidence of ARC in patients with a normal serum creatinine concentration, clinicians should consider screening ICU patients deemed high risk by using the ARC scoring system or the identification and assessment algorithm provided in this review. In addition, an 8-hour continuous urine collection should be considered to assess a measured creatinine clearance for evaluating the necessity of medication dosage adjustments. There is a clear association between ARC and subtherapeutic antibiotic concentrations as well as literature suggesting worse clinical outcomes; thus, the risk of underdosing antibiotics in a patient with ARC could increase the risk of treatment failure. This review examines strategies to overcome ARC and summarizes current pharmacokinetic and pharmacodynamic literature in patients with ARC in an effort to provide dosing guidance for this patient population.

Population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese and nonobese patients.

The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese and nonobese patients. Twenty-seven patients (total body weight [TBW], 60 to 211 kg; body mass index [BMI], 19.6 to 72.9 kg/m(2) ) received 4.5 or 6.75 g every 8 hours, infused over 4 hours, and serum concentrations were measured at steady state. Population pharmacokinetic parameters were estimated using NONMEM, and Monte Carlo simulations were performed for three 4-hour dosing regimens to calculate probability of target attainment (PTA) at ≥50% fT>MIC.A 1-compartment linear-elimination model best fit the pharmacokinetic data for piperacillin and tazobactam. Creatinine clearance (CRCL), TBW, and BMI were significantly associated with piperacillin pharmacokinetics, and CRCL was significantly associated with tazobactam pharmacokinetics. Clearance and volume of distribution for piperacillin and tazobactam were significantly different between obese and nonobese patients (P < .05). At MICs ≤ 16 mg/L, PTA was >90% for dosing regimens ≥3.375 g every 8 hours in nonobese patients and ≥ 4.5 g every 8 hours in obese patients. Piperacillin and tazobactam pharmacokinetics are altered in obesity, and 4.5 g every 8 hours infused over 4 hours should be recommended for empiric therapy in obese patients.

Steady-state pharmacokinetics and pharmacodynamics of meropenem in morbidly obese patients hospitalized in an intensive care unit.

The study objective was to evaluate meropenem pharmacokinetics and pharmacodynamics in morbid obesity. Nine patients hospitalized in an intensive care unit with a body mass index ≥40 kg/m(2) received meropenem 500 mg or 1 g q6h, infused over 0.5 hours. Pharmacokinetic parameters were estimated, and Monte Carlo simulations were performed for 5 dosing regimens (500 mg q8h, 1 g q8h, 2 g q8h, 500 mg q6h, 1 g q6h) infused over 0.5 and 3 hours. Probability of target attainment (PTA) was calculated using fT > MIC of 40% and 54%. Total body weight and body mass index were 152.3 ± 31.0 kg and 54.7 ± 8.6 kg/m(2) , respectively. Volume of distribution of the central compartment was 13.3 ± 6.7 L, volume of distribution at steady-state was 37.4 ± 14.7 L, and systemic clearance was 10.2 ± 5.0 L/h. At an MIC of 2 µg/mL, PTA was ≥90% for 4/5 and 2/5 regimens infused over 0.5 hours and for 5/5 and 4/5 regimens infused over 3 hours at 40% and 54% fT > MIC, respectively. Standard doses achieve adequate exposures for susceptible bacteria at a pharmacodynamic target of 40% fT > MIC. Higher doses or prolonged infusion regimens are needed at the higher pharmacodynamic target.

Steady-state pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese patients.

The study objective was to evaluate steady-state pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese patients. Fourteen hospitalised patients weighing >120kg received piperacillin/tazobactam 4.5 g every 8 h (q8h) or 6.75 g q8h infused over 4h. Blood samples were collected at steady-state and drug concentrations were determined. Pharmacokinetic parameters were estimated and 5000-patient Monte Carlo simulations were performed for four prolonged-infusion dosing regimens. The probability of target attainment (PTA) for ≥50% fT>MIC was calculated for piperacillin at various MICs, and the PTA for fAUC(0-24)≥96 mg h/L was calculated for tazobactam. Mean±S.D. patient demographics were: age 49±10 years; weight 161±29 kg; and body mass index 52.3±10.8 kg/m(2). For piperacillin and tazobactam, respectively, the mean±S.D. elimination rate was 0.440±0.177 h(-1) and 0.320±0.145 h(-1), volume of distribution was 33.4±14.0L (0.21±0.07L/kg) and 37.5±15.3L (0.23±0.08 L/kg), and systemic clearance was 13.7±5.2L/h and 11.1±4.2L/h. For piperacillin, the PTA was ≥91% for doses ≥4.5g q8h at MICs≤16 µg/mL. For tazobactam, the PTA was 57%, 84% and 94% for doses of 4.5, 6.75 and 9.0g q8h, respectively. The pharmacokinetics of piperacillin and tazobactam are altered in obese patients. To ensure adequate tazobactam concentrations for ß-lactamase inhibition, it may be prudent to employ larger initial doses for empirical therapy in obese patients.

Steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients.

The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients requiring antimicrobial therapy. Nine patients received 1g every 8h (q8h), infused over 4h, and steady-state pharmacokinetic parameters were determined by non-compartmental and compartmental methods. Using these pharmacokinetic parameters, 5000-patient Monte Carlo simulations were performed to estimate the pharmacokinetic profiles for six prolonged-infusion dosing regimens. The probability of target attainment (PTA) was calculated at minimum inhibitory concentrations (MICs) ranging from 0.06 µg/mL to 32 µg/mL, and the cumulative fraction of response (CFR) was calculated for six Gram-negative pathogens using MIC data from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) (2005-2007, USA). The pharmacodynamic target was free cefepime concentrations remaining above the MIC for 60% of the dosing interval (60% fT>MIC). Mean ± standard deviation maximum and minimum serum concentrations, terminal elimination half-life, elimination rate constant, volume of distribution and systemic clearance of cefepime were 32.5 ± 13.5 µg/mL, 9.5 ± 5.2 µg/mL, 2.4 ± 0.7h, 0.316 ± 0.116 h(-1), 21.3 ± 6.5L and 6.6 ± 3.6L/h, respectively. At the susceptibility breakpoint of 8 µg/mL, the PTA was >90% for 1g and 2g q8h (4-h infusion) and 1g and 2g every 6h (q6h) (3-h infusion). For Pseudomonas aeruginosa, the CFR was 88.6% for 1g q8h (4-h infusion) and ≥ 92.7% for 2g q8h (4-h infusion) and 1g and 2g q6h (3-h infusion). Cefepime 1g q8h infused over 4h provides excellent target attainment for susceptible bacterial pathogens with MICs ≤8 µg/mL.