Changes in essential care in individuals with spinal cord injury during the COVID-19 pandemic.

STUDY DESIGN: Cross-sectional, observational study. OBJECTIVES: To determine whether changes in essential care during the COVID-19 pandemic impacted satisfaction with activities, participation, and relationships among individuals with spinal cord injury (SCI). SETTING: Data were collected online between December 31, 2020 and February 14, 2021 among community dwelling adults with SCI (N = 123). METHODS: The primary outcome variables were satisfaction with the ability to complete activities of daily living (ADLs) (mobility, dressing, feeding, and toileting), as well as satisfaction with participation in household and recreational activities, and satisfaction with relationships among friends, family, and with the status of one's relationship measured with the International Spinal Cord Injury Data Sets Activities and Participation Basic Data Set. Primary predictors were age, gender, time since injury, completeness of injury, injury level, access to mental health, access to medications, access to medical supplies, and access to personal care assistants (PCAs). RESULTS: Impact on access to mental health and impact on access to supplies were the most common factors affecting satisfaction with activities, participation, and relationships for individuals with SCI during the COVID-19 pandemic. Impact on access to PCAs/homecare was also found to impact certain outcomes including feeding and participation in household activities. CONCLUSIONS: Future supply chain disruptions from pandemics or natural disasters could have wide-reaching effects for individuals with SCIs. Thus, further research and advocacy is needed to improve mental health care planning and supply chain access during subsequent natural disasters.

Three-Year Results of a Medicare Advantage Cancer Management Program.

PURPOSE: Reform of cancer care delivery seeks to control costs while improving quality. Texas Oncology collaborated with Aetna to conduct a payer-sponsored program that used evidence-based treatment pathways, a disease management call center, and an introduction to advance care planning to improve patient care and reduce total costs. METHODS: From June 1, 2013, to May 31, 2016, 746 Medicare Advantage patients with nine common cancer diagnoses were enrolled. Patients electing for patient support services were telephoned by oncology nurses who assessed symptoms and quality of life and introduced advance care planning. Shared cost savings were determined by comparing the costs of drugs, hospitalization, and emergency room use for 509 eligible patients in the study group with a matched cohort of 900 Medicare Advantage patients treated by non-Texas Oncology providers. Physician adherence to treatment pathways and performance and quality metrics were evaluated. RESULTS: During the 3 years of the study, the cumulative cost savings were $3,033,248, and savings continued to increase each year. Drug cost savings per patient per treatment month were $1,874 (95% CI, $1,373 to $2,376; P < .001) after adjusting for age, diagnosis, and study year. Solid tumors contributed most of the savings; hematologic cancers showed little savings. For years 1, 2, and 3, adherence to treatment pathways was 81%, 84%, and 90%, patient satisfaction with patient support services was 94%, 93%, and 94%, and hospice enrollment was 55%, 57%, and 64%, respectively. CONCLUSION: A practice-based program supported by a payer sponsor can reduce costs while maintaining high adherence to treatment pathways and patient satisfaction in older patients.

Pseudomonas aeruginosa is not just in the intensive care unit any more: implications for empirical therapy.

OBJECTIVE: To improve empirical therapy for Pseudomonas aeruginosa using susceptibility surveillance by unit type (intensive care unit vs. nonintensive care unit) and to optimize antibacterial dosing using pharmacodynamic profiling. DESIGN: Prospective multicentered surveillance study. SETTING: Thirteen U.S. hospitals. SUBJECTS: Seven hundred thirty-six nonduplicate, nonurine P. aeruginosa isolates collected from first quarter, 2009, to second quarter, 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Isolate minimum inhibitory concentrations (MICs) to ten antimicrobials (three carbapenems-doripenem, imipenem and meropenem-plus three other ß-lactams, two fluoroquinolones, and two aminoglycosides) were determined by broth microdilution. Wilcoxon rank sums compared MIC distributions by unit type; chi-square tests compared agents and antibiotic classes. Cumulative fraction of response predicted likelihood of pharmacodynamic target attainment for antimicrobial dosing regimens vs. observed MIC distributions. Nonintensive care units contributed 65% of isolates with identifiable locations (n = 614). Carbapenem class nonsusceptibility nonsusceptible to 1 or more agent) differed by location (35% intensive care unit, 27% nonintensive care unit, p = .03); no other classes differed. Multidrug resistance (nonsusceptible to one or more drug in each of all four classes) was 12% intensive care unit and 5% in nonintensive care units (p < .01). Carbapenem MIC profile in intensive care units was (agent, MIC50, MIC90, percent susceptibility): Doripenem, 1, 8, 69%; imipenem, 2, 16, 67%; and meropenem, 1, 32, 70%; and by nonintensive care units: Doripenem, 0.5%, 8%, 78%; imipenem, 1, 16, 75%; and meropenem, 1, 16, 82%. MIC distributions differed by unit type only for imipenem (p < .01). The remaining nine agents were not different. Standard carbapenem regimens resulted in cumulative fraction of response (regimen, intensive care unit, nonintensive care unit): Doripenem at 500 mg every 8 hrs 1-hr infusion, 73%, 79%; imipenem at 500 mg every 6 hrs 0.5-hr infusion, 62%, 69%; meropenem at 500 mg every 6 hrs 0.5-hr infusion, 67%, 76%. More aggressive doses and prolonged infusion improved cumulative fraction of response: Doripenem at 1000 mg every 8 hrs 4-hr infusion, 92%, 97%; imipenem at 1000 mg every 8 h 3-h infusion, 77%, 83%; meropenem at 2000 mg every 8 hrs 3-hr infusion, 87%, 94%. CONCLUSIONS: Although multidrug-resistant and nonsusceptible carbapenem phenotypes were more common in intensive care units, the prevalence of P. aeruginosa among initial cultures of systemic isolates taken elsewhere was high (65%). Unit-specific antibiograms could benefit empirical therapy decisions; consideration of carbapenem, dose, and infusion time may enhance outcomes for P. aeruginosa infection.

Selection of prophylactic antimicrobial agent may affect incidence of infection in small bowel and colorectal surgery.

BACKGROUND: Antibiotic prophylaxis guidelines suggest single-dose regimens are adequate, but comparisons of multiple agents are lacking. We compared post-operative infection rates retrospectively among six common prophylactic agents given as a single dose to colorectal surgery patients. METHODS: A commercial database supplied demographics, All-Patient Refined Diagnosis-Related Groups (APR DRGs), International Classification of Disease (ICD)-9 codes, and drug utilization information for patients discharged from 303 hospitals from January 2007-December 2008 whose charts had been sampled for reporting Surgical Care Improvement Project (SCIP) measures. The patients (n=4,634) had the same APR DRG, no baseline infection, and prophylaxis discontinued within 24 h of surgery. Development of infection was determined by ICD-9 code. "Single dose" was defined as ≤3 g of ampicillin-sulbactam (AMP); ≤2 g of cefotetan (CFT), cefoxitin (FOX), or ertapenem (ERT); or metronidazole and ≤2 g of cefazolin (CFZ) or ≤750 mg of levofloxacin (LVX) given on the day of the procedure. Multivariable logistic regression evaluated factors associated with infection, including agent choice. RESULTS: Frequency of use and rate of infection (3.7% overall) were FOX 1,752 (4.9%), ERT 1,166 (2.7%), CFZ 549 (2.7%), AMP 447 (3.6%), LVX 402 (3.2%), and CFT 318 (3.5%). The unadjusted infection rate differed by agent (p=0.037). Multiple regression analysis found infection to be associated significantly with increasing APR DRG severity, longer procedures, younger age, and male gender (p<0.01 for each except p=0.02 for age), as well as agent choice. Among agents (vs. FOX as reference), ERT was associated with a lower infection rate (odds ratio 0.53; 95% confidence interval 0.34-0.82; p<0.01); the odds ratio for all other agents contained the value 1.0. CONCLUSIONS: Agent selection among prophylactic antibiotics is one of many factors associated with infection development in colorectal surgery patients.

Change in antipseudomonal carbapenem susceptibility in 25 hospitals across 9 years is not associated with the use of ertapenem.

BACKGROUND: Concern remains that ertapenem use may promote cross-resistance in Pseudomonas aeruginosa to antipseudomonal carbapenems (APCs). This study extends our earlier multicentre investigation of this relationship by an additional 3 years. METHODS: Use density ratios (UDRs) for ertapenem, APCs, aminoglycosides, fluoroquinolones and non-carbapenem ß-lactams were derived from purchase data for 3 years pre-adoption and up to 6 years post-adoption of ertapenem at 25 hospitals. Hospital antibiograms in corresponding years yielded APC susceptibility data. Mixed model repeated measures ANOVA explored associations between 9 year repeated APC susceptibility and ertapenem UDR while controlling for all other classes. RESULTS: All 25 sites had 4 years of post-adoption data, with 22 of 25 reporting 5 years and 18 of 25 reporting 6 years. Ertapenem UDR rose steadily once adopted, with a mean UDR of 7.27 in year 4 and a mean UDR of 15.93 in year 9. APC UDR increased initially (from 10.39 in year 1 to a peak of 18.77 in year 6) and then declined to 15.27 in year 9. By year 9 ertapenem and APC use were similar. Among other classes, fluoroquinolone UDR increased notably (year/mean UDR): 1/303.84; 4/174.38; and 9/423.32. Mean APC susceptibility declined from 85.4% in year 1 to 81.0% in year 9; this change across time was not significant (P = 0.99). Change in 9 year APC susceptibility was not associated with ertapenem UDR (P = 0.54), while controlling for all other antibiotic classes (all showed no association at P > 0.5). CONCLUSIONS: While controlling for utilization of other antibiotic classes, we found no association between change in APC susceptibility and ertapenem use.

Fluoroquinolone use is not associated with the change in imipenem susceptibility of Pseudomonas aeruginosa in 25 hospitals.

INTRODUCTION: Evidence suggests use of fluoroquinolones is associated with carbapenem resistance in Pseudomonas aeruginosa, and fluoroquinolone use has been identified as a risk factor for clinical acquisition of imipenem-resistant P. aeruginosa in single-center studies. Imipenem susceptibility and fluoroquinolone use was evaluated within 25 hospitals over 9 years. METHODS: Use density ratios (UDR) for fluoroquinolones: ciprofloxacin, gatifloxacin, levofloxacin, and moxifloxacin, and for three other antibiotic classes (carbapenems: ertapenem, doripenem, imipenem, and meropenem; other antipseudomonal beta-lactams: cefepime, ceftazidime, and piperacillin/tazobactam; and aminoglycosides: gentamicin and tobramycin) were derived from drug purchase data for up to 9 years, ending in 2008. Susceptibility data were obtained from hospital antibiograms in corresponding years. A mixed model repeated measures ANOVA (Analysis of Variance) explored associations between 9-year repeated imipenem susceptibility and fluoroquinolone UDR in each year while controlling for other drug classes, teaching status, and number of beds. RESULTS: All sites had 7 years of data; n=22 had 8 years; n=18 had 9 years. Teaching hospitals were 36% of the cohort; median number of beds was 714 for teaching hospitals and 381 for nonteaching hospitals. Fluoroquinolone use declined from year (Y) 1-5; such use then rose over Y6-9, which was heavily influenced by ciprofloxacin/moxifloxacin: mean fluoroquinolone UDR from Y1-9 was: 303.8, 186.5, 156.8, 174.4, 169.1, 275.0, 504.2, 477.0, and 423.3. Mean imipenem susceptibility was (Y1-9 %) 85.2, 82.8, 82.7, 82.2, 82.8, 82.4, 82.3, 81.7, and 80.6; this change across time was not significant (P=0.46). Change in 9-year imipenem susceptibility was not associated with fluoroquinolone UDR (P=0.17), nor with any other drug class (P>0.40 for each). Results were not different when considering only sites with top 25% fluoroquinolone UDR during Y7-9. CONCLUSION: Single-center studies of fluoroquinolone use have reported changes in P. aeruginosa susceptibility to carbapenems. Our study finds no such association while controlling for other drug classes. As such, resistance development in individual patients versus institutions warrants further research.

Length of stay and hospital costs associated with a pharmacodynamic-based clinical pathway for empiric antibiotic choice for ventilator-associated pneumonia.

STUDY OBJECTIVE: To determine hospital costs associated with the use of a clinical pathway implemented in our intensive care units (ICUs) to optimize antibiotic regimen selection for patients with ventilator-associated pneumonia (VAP) compared with costs in a historical control group treated according to prescriber preference. DESIGN: Retrospective cost analysis from the hospital perspective. SETTING: Single, tertiary-care medical center. PATIENTS: One hundred sixty-six adults with VAP from the medical, surgical, and neurotrauma ICUs (73 historical control patients [2004-2005] and 93 patients given an empiric antibiotic clinical pathway for VAP [2006-2007]). MEASUREMENTS AND MAIN RESULTS: The VAP clinical pathway consisted of an ICU-specific three-drug regimen that considered local minimum inhibitory concentration distributions and a pharmacodynamically optimized dosing strategy. Hospital cost data were collected and inflated to 2007 according to the consumer price index. The VAP-related length of treatment, hospitalization costs, and antibiotic costs were compared between groups. The median VAP length of treatment was 24 days (interquartile range [IQR] 13-35 days] and 11 days (IQR 7-17 days) for historical and clinical pathway groups, respectively (p<0.001). Daily hospital costs were similar for both cohorts over the first 7 days, after which costs declined significantly for patients treated with the clinical pathway (p<0.001). When controlling for baseline differences between groups and length of stay before development of VAP, patients treated with the clinical pathway had shorter lengths of ICU stay after VAP, shorter total hospital lengths of stay after VAP, and lower hospital costs after the treatment of VAP. Median total antibiotic costs for individual patients were similar between groups ($535 [IQR $261-998] vs $482 [IQR $222-985] clinical pathway vs control, p=0.45), and the proportion of VAP hospital resources consumed by antibiotics for both groups was low. CONCLUSION: Although aggressive dosing of more costly antibiotics was empirically prescribed using the clinical pathway, patients in this group exhibited a shorter duration of treatment, reduced hospital length of stay after VAP, and lower hospital costs without any significant increase in antibiotic expenditures.

Absence of association between use of ertapenem and change in antipseudomonal carbapenem susceptibility rates in 25 hospitals.

OBJECTIVE: Ertapenem exposure has been reported to select for cross-resistance to other carbapenems in Pseudomonas aeruginosa in vitro. Single-center investigations report conflicting results. We evaluated ertapenem use and antipseudomonal carbapenem susceptibility for 6 years spanning the time of ertapenem adoption at each of 25 US hospitals. DESIGN: Retrospective primary and secondary data analysis. METHODS: Use density ratios for imipenem and meropenem (collectively, "other carbapenems") and ertapenem were derived from data in a commercial database on the total number of grams used in the 3 years before and the 3 years after adoption of ertapenem at each hospital. A general linear model using repeated measures analysis of variance was used to explore associations between the 6-year change in antipseudomonal carbapenem susceptibility rates (determined from hospital antibiograms) and ertapenem use in each year, while controlling for other carbapenem use. RESULTS: Ertapenem use increased once adopted. With regard to the postadoption period, the median use density ratio for year 4 was 4.1 (interquartile range [IQR], 1.7-5.2), for year 5 was 6.0 (IQR, 2.7-8.5), and for year 6 was 6.5 (IQR, 4.0-11.6). The median use density ratio for other carbapenem use for year 1 was 8.7 (IQR, 5.7-13.5), and by year 6 it had increased to 19.3 (IQR, 9.6-26.2). Change in mean antipseudomonal carbapenem susceptibility across time (85% in year 1 to 82% in year 6) was not significant (P = .22). Change in 6-year antipseudomonal carbapenem susceptibility was not associated with ertapenem use in any year while controlling for other carbapenem use (P > .20 for all years of ertapenem use). CONCLUSION: Although significant change in P. aeruginosa susceptibility to antipseudomonal carbapenems was not detected during this multicenter study, which to our knowledge is the most extensive assessment to date of this important drug use-susceptibility relationship, continued evaluation of the relationship is prudent.

Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia.

BACKGROUND: Because of the high frequency of multidrug resistant bacteria in our intensive care units (ICUs), we implemented a ventilator-associated pneumonia (VAP) clinical pathway based on unit-specific minimum inhibitory concentration (MIC) distributions and pharmacodynamic modeling in 3 of our ICUs. METHODS: This was a prospective, observational evaluation with a historical control group in adult patients (n = 168) who met clinical and radiologic criteria for VAP. Monte Carlo simulation was used to determine antibiotic regimens having the greatest likelihood of achieving bactericidal exposures against Pseudomonas aeruginosa. Antibiotic regimens were incorporated into an ICU-specific computerized clinical pathway as empiric agents of choice. RESULTS: Pharmacodynamic modeling found 3-hour infusions of cefepime 2 g every 8 hours or meropenem 2 g every 8 hours plus tobramycin and vancomycin would provide the greatest probability of empirically treating VAP in these ICUs. Infection-related mortality was reduced by 69% (8.5% vs 21.6%; P = .029), infection-related length of stay was shorter (11.7 +/- 8.1 vs 26.1 +/- 18.5; P < .001), and fewer superinfections were observed in patients treated on the pathway. A number of patients with nonsusceptible P aeruginosa were successfully treated with high-dose, 3-hour infusion regimens. CONCLUSIONS: In our ICUs where multidrug resistant bacteria are common, an approach considering ICU-specific antibiotic MICs coupled with pharmacodynamic dosing strategies resulted in improved outcomes and shorter duration of treatments.

Surgical site infections: does inadequate antibiotic therapy affect patient outcomes?

BACKGROUND: Complicated skin/skin structure infections involve deeper soft tissues and include surgical site infections (SSIs). Inadequate antibiotic therapy (IAT) has been associated with adverse outcomes in respiratory and blood stream infections, but is seldom evaluated in SSIs. This study assessed the impact of IAT on primary outcomes of length of stay (LOS) and costs in complicated SSIs; identifying risk factors associated with receiving IAT was a secondary objective. METHODS: This retrospective cohort study of discharges from our 810-bed urban teaching hospital from Quarter 4/2004-Quarter 1/2006 identified 130 patients with complicated SSI among 298 patients with postoperative infections. Superficial infections and infections not involving the skin/skin structures were excluded. Patient characteristics, culture data, and antibiotic history were collected from charts. Inadequate antibiotic therapy was said to have occurred when a drug active against the organism cultured was not given within 24 h of culture. Multiple regression identified variables associated with LOS and increase hospital accounting costs. RESULTS: A total of 39 subjects (30%) received IAT; patient characteristics did not differ from those receiving adequate therapy, except that prior antibiotic use was more likely in IAT subjects (p = 0.053). Staphylococcus aureus (45% methicillin-resistant) was the most common pathogen (39%). More than one-half (60%) of the subjects received empiric vancomycin. The IAT patients experienced longer post-infection LOS and higher costs (median [25%, 75%]): 10 [6, 21] days vs. 7 [4, 11] days; p = 0.007 and $11,746 [$6,652, $28,442] vs. $7,116 [$5,210, $16,443]; p = 0.04). Longer LOS was associated significantly with Acute Physiology and Chronic Health Evaluation score, IAT, Pseudomonas infection, and sternal incisions, as were higher costs, excepting Pseudomonas infection. Inadequate antibiotic therapy was more likely in polymicrobial infections (p < 0.001), pseudomonal (p < 0.001) or enterococcal (p = 0.002) infections, and infected abdominal incisions (p < 0.001). Methicillin-resistant S. aureus was not associated with adverse outcomes, possibly because empiric therapy frequently included vancomycin. CONCLUSIONS: Inadequate antibiotic therapy is associated with longer LOS and higher costs in complicated SSIs. Risk factors for IAT include prior antibiotic therapy, polymicrobial infection, infection with P. aeruginosa or Enterococcus spp., and abdominal incisions.

Risk factors and outcomes associated with isolation of meropenem high-level-resistant Pseudomonas aeruginosa.

OBJECTIVE: To determine risk factors and outcomes for patients with meropenem high-level-resistant Pseudomonas aeruginosa (MRPA) (minimum inhibitory concentration [MIC] > or = 32 microg/mL). DESIGN: Case-control-control. SETTING: An 867-bed urban, teaching hospital. PATIENTS: Fifty-eight MRPA case patients identified from an earlier P. aeruginosa study; 125 randomly selected control patients with meropenem-susceptible P. aeruginosa (MSPA) (MIC < or = 4 microg/mL), and 57 control patients without P. aeruginosa (sampled by case date/location). METHODS: Patient data, outcomes, and costs were obtained via administrative database. Cases were compared to each control group while controlling for time at risk (days between admission and culture, or entire length of stay [LOS] for patients without P. aeruginosa). RESULTS: A multivariable model predicted risks for MRPA versus MSPA (odds ratio [95% confidence interval]): more admissions (in the prior 12 months) (1.41 [1.15, 1.74]), congestive heart failure (2.19 [1.03, 4.68]), and Foley catheter (2.53 [1.18, 5.45]) (adj. R(2) = 0.28). For MRPA versus no P. aeruginosa, risks were age (in 5-year increments) (1.17 [1.03, 1.33]), more prior admissions (1.40 [1.08, 1.81]), and more days in the intensive care unit (1.10 [1.03, 1.18]) (adj. R(2) = 0.32). Other invasive devices (including mechanical ventilation) and previous antibiotic use (including carbapenems) were nonsignificant. MRPA mortality (31%) did not differ from that of MSPA (15%) when adjusted for time at risk (P = .15) but did from mortality without P. aeruginosa (9%) (P = .01). Median LOS and costs were greater for MRPA patients versus MSPA patients and patients without P. aeruginosa: 30 days versus 16 and 10 (P<.01) and $88,425 versus $28,620 and $22,605 (P<.01). CONCLUSIONS: Although antibiotic use has been shown to promote resistance, our data found that prior antibiotic use was not associated with MRPA acquisition. However, admission frequency and Foley catheters were, suggesting that infection control measures are essential to reducing MRPA transmission.

Deep and organ/space infections in patients undergoing elective colorectal surgery: incidence and impact on hospital length of stay and costs.

BACKGROUND: The reported incidence of infection complicating elective colorectal surgery (ECS) is 11% to 26%. We evaluated length of stay (LOS) and expense associated with such infections, which heretofore remain unexplored. METHODS: We reviewed 1127 ECS procedures from October 2005 to may 2007 to identify infected case subjects (n = 46). Data were obtained by way of chart abstraction and administrative database review. A case-control study evaluated LOS and actual accounting costs for case subjects versus uninfected control subjects (n = 46). Logistic regression determined risk factors for infection. RESULTS: Infection incidence was 4.1%. Mean +/- SD LOS and costs were greater for case than control subjects: 21 +/- 15 days compared with 6 +/- 4 days (P < .001) and $42,516 +/- 39,972 compared with $10,999 +/- $7,122 (P < .001). Procedure type, infection, chronic obstructive pulmonary disease, increased age, and nonsmoking status predicted greater LOS and costs. Infection risk factors included duration of procedure > or =3 hours, male sex, higher American Society of Anesthesiologists (ASA) score, low baseline hematocrit, and indication for surgery of regional enteritis/ulcerative colitis. COMMENTS: Infection development after ECS is infrequent in our population, but it results in significantly poorer outcomes. Vigilant adherence to preventive guidelines, including those for antibiotic prophylaxis, is warranted.

Impact of superinfection on hospital length of stay and costs in patients with ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) increases length of stay (LOS) in VAP versus non-VAP patients, but LOS differences among VAP patients remain unexplained. We explored the economic impact of developing a respiratory superinfection while being treated for VAP. This was a retrospective, observational cohort study conducted in 74 patients discharged between January 2004 and July 2005 identified as having VAP. Using detailed, chart-abstracted demographic and hospital-course data--including antibiotic therapy, APACHE II scores, and superinfection development--multivariable analysis determined variables independently associated with LOS and total accounting costs from the date of VAP identification (VAP ID) to discharge or death. Overall mortality and mean +/- SD APACHE II were 35% and 19.4 +/- 8.9 for 74 cases; 35% of the cohort developed a superinfection. Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella spp. were most frequently responsible. Mortality was unaffected by superinfection. Younger age (P = 0.003), superinfection (P = 0.006), and admission to the surgical intensive care unit (ICU) (P = 0.014) independently predicted LOS (adjusted R(2) = 0.296). Younger age (P < 0.001), admission to the surgical ICU (P = 0.004), superinfection (P = 0.002), and previous antibiotic exposure (P = 0.009) predicted increased costs (adjusted R(2) = 0.394). Mean (95% CI) LOS and total costs after contracting VAP were greater for superinfection patients [47.8 days (39.0 to 56.5) versus 27.9 (22.4 to 33.1), P < 0.001; $140,850 ($98,426 to $183,275) versus $73,801 ($58,946-$88,656), P < 0.001], with 15.6 days and $48,527 attributable to superinfection. While not affecting mortality in those patients with VAP, superinfections independently predict increased LOS after VAP ID, contributing to substantial additional cost.

In vitro activity and pharmacodynamics of commonly used antibiotics against adult systemic isolates of Escherichia coli and Pseudomonas aeruginosa at Forty US Hospitals.

BACKGROUND: Treatment of infections caused by gram-negative bacilli is increasingly challenging because of emerging resistance. Current surveillance data are informative, but may not discern differences by infection site and clinical setting, and do not incorporate pharmacodynamic (PD) characteristics when determining susceptibility. OBJECTIVES: This study explored the differences in infection site and clinical setting and evaluated dose-optimization strategies using PD principles. The stud focused only on systemic isolates, and targeted a cohort of 40 hospitals in the United States with a nationwide geographic distribution. METHODS: Nonduplicate, nonurine isolates of Escherichia coli (n = 937) and Pseudomonas aeruginosa (n = 1044) collected from adult patients at 40 US hospitals underwent MIC testing by broth microdilution to 15 agents. Results were analyzed by infection site and unit type (ward or intensive care unit [ICU]). PD modeling employing Monte Carlo simulation was used to predict the microbiologic success of varying dosing strategies. RESULTS: E coli were highly susceptible except to fluoroquinolones; 6.8% were multidrug resistant (MDR) and were more likely in ICUs (risk ratio [RR], 2.5; 95% CI, 1.6-4.0). P aeruginosa displayed 90% for most drug classes), with the important exception of the fluoroquinolones; however, susceptibility of P aeruginosa is low enough to warrant concern. Attention to the source of the organism and the patient's location in an ICU or a ward-combined with knowledge of local epidemiology and PD principles--should prove valuable in empiric agent selection. Additionally, reassessment of breakpoints employing PD principles is recommended, particularly for fluoroquinolones and piperacillin/tazobactam.

A pharmacodynamic analysis of resistance trends in pathogens from patients with infection in intensive care units in the United States between 1993 and 2004.

BACKGROUND: Increasing nosocomial pathogen resistance to available antimicrobial agents is of growing concern. While higher MICs can diminish antimicrobial effectiveness, dose adjustments often mitigate this effect. This study's objective was to ascertain whether MICs among major pathogens in the ICU to several commonly used agents have increased enough to significantly impact their ability to achieve bactericidal effect. METHODS: Cefepime, ceftriaxone, imipenem and piperacillin-tazobactam MICs were determined with 74,394 Gram-negative bacilli obtained from ICU patients with various infections in the US between 1993 and 2004. Results were grouped into four 3-year periods. The predicted cumulative fraction of response (CFR) was estimated based on patient-derived pharmacokinetic values and Monte Carlo simulation. Trends in CFR over the four study periods were assessed using the Cochran-Armitage test. The primary analysis included all organisms combined; Pseudomonas aeruginosa and Acinetobacter species were also evaluated individually. RESULTS: In the primary analysis, imipenem 500 mg q6h showed CFRs from 87% to 90% across all four study periods, with a trend toward slightly improved bactericidal target attainment (p < 0.01). CFRs for cefepime 2 g q12h and piperacillin-tazobactam 4.5 g q6h both declined by 2% (p < 0.01 and p < 0.05, respectively), reflecting upward shifts in the underlying MIC distributions. Ceftriaxone had <52% CFR for all regimens in all periods, with no significant trend. Against P. aeruginosa, significant declines in CFR were seen for (range, p-value): imipenem 1 g q8h (82%-79%, p < 0.01), cefepime 1 g q12h (70%-67%, p < 0.01), cefepime 2 g q12h (84%-82%, p < 0.05), piperacillin-tazobactam 3.375 g q6h (76%-73%, p < 0.01), piperacillin-tazobactam 4.5 g q8h (71%-68%, p < 0.01), and piperacillin-tazobactam 4.5 g q6h (80%-77%, p < .01). Against Acinetobacter spp., all regimens of imipenem, cefepime and piperacillin-tazobactam showed significant declines in CFR over time (p < 0.01). CONCLUSION: Our observations suggest that as a result of increasing antimicrobial resistance among ICU pathogens in the US, drug effectiveness, assessed as a function of individual agents' ability to attain pharmacodynamic targets, has declined, especially with P. aeruginosa and Acinetobacter spp. Cefepime 2 g q8h and imipenem were the most potent agents against these species, respectively. More aggressive dosing of all of the agents characterized could preserve their clinical utility, but this must be balanced with safety and tolerability issues by the physician.

Empiric therapy for secondary peritonitis: a pharmacodynamic analysis of cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, piperacillin/tazobactam, and tigecycline using Monte Carlo simulation.

BACKGROUND: Inappropriate antibiotic therapy (ie, the selection of an empiric agent without activity against the responsible pathogen) of secondary peritonitis may result in poor patient outcomes. The selection of an appropriate agent can be challenging because of the emerging resistance of target organisms to commonly prescribed antibiotics. OBJECTIVE: The aim of this study was to perform a pharmacodynamic analysis, using recent global surveillance data, of commonly prescribed antibiotic agents and a newer agent, tigecycline, indicated in 2005 for the treatment of complicated intra-abdominal infections, to determine their probability for achieving microbiologic success against aerobic bacteria associated with secondary peritonitis. METHODS: A 2-compartment model was constructed using pharmacokinetic data from critically ill patients and global surveillance data on MIC distributions for microorganisms encountered in secondary peritonitis. A Monte Carlo simulation of the modeled data was performed to determine drug-appropriate pharmacodynamic end points, including free-drug time above the MIC, steady-state concentration above the MIC, and AUC/MIC ratios. A cumulative fraction of response (CFR) against aerobic bacteria involved in secondary peritonitis was calculated for cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, pip eracillin/tazobactam, and tigecycline. A CFR > or =90% was considered microbiologic success. The following treatment regimens, administered as 30-minute N infusions, were examined: cefepime 1 and 2 g q12h, ceftazidime 1 and 2 g q8h, ceftriaxone 1 and 2 g q24h, imipenem 500 mg q6h, levofloxacin 750 mg q24h, pip eracillin/tazobactam 3.375 g q6h, and tigecycline 50 mg q12h, after a loading dose of 100 mg. RESULTS: A CFR > or =90% against nonenterococcal bacteria was predicted for imipenem 500 mg q6h (96.8%), cefepime 2 and 1 g q12h (95.3% and 92.4%, respectively), ceftazidime 2 g q8h (94.2%), and piperacillin/tazobactam 3.375 g q6h (91.2%). A CFR of 84.5% was predicted for tigecycline 50 mg q12h. Ceftriaxone and levofloxacin were predicted to have a CFR <80%. When enterococci were included in the model, the predicted CFRs for imipenem, piperacillin/tazobactam, and tigecycline were 93.4%, 88.4%, and 86.7%, respectively. CONCLUSIONS: : MIC distribution and pathogen prevalence strongly influence the likelihood of microbiological success in secondary peritonitis; therefore, decisions regarding empiric therapy should consider local epidemiology. Using current global data, the following regimens are adequate choices if Enterococcus is not targeted: Combination therapy (with metronidazole) using cefepime 1 g or 2 g q12h, or ceftazidime 2 g q8h; or monotherapy with imipenem 500 mg q6h or piperacillin-tazobactam 3.375 g q6h. When Enterococcus is included in the epidemiologic mix, imipenem, piperacillin/tazobactam, and tigecycline all appear to be viable monotherapeutic choices.

Evaluating empiric treatment options for secondary peritonitis using pharmacodynamic profiling.

BACKGROUND: Selecting an appropriate agent for empiric antibiotic therapy for secondary peritonitis is challenging. The pathogens responsible, aerobic gram-negative bacilli in particular, are becoming more resistant to antibiotics. The purpose of this study was to predict the ability of common antimicrobial regimens to achieve optimal pharmacodynamic exposure against aerobic bacteria implicated in secondary peritonitis, while considering current national resistance trends. METHODS: Monte Carlo simulation was used to model pharmacodynamic endpoints and compare the cumulative fraction of response (CFR) for imipenem-cilastatin, meropenem, ertapenem, piperacillin/tazobactam, ceftazidime, ceftriaxone, ciprofloxacin, and levofloxacin against isolates of species associated with secondary peritonitis. Minimum inhibitory concentration (MIC) distributions for isolates collected in North America were obtained from the 2004 MYSTIC database. Pharmacokinetic parameters were derived from the literature; the endpoints evaluated included free drug time above the MIC (fT(>MIC)) and the area under the concentration-time curve to MIC ratio (AUC:MIC). RESULTS: The simulation predicted that several compounds would have a superior probability of providing appropriate coverage of aerobic bacteria: Imipenem-cilastatin (98.6% CFR at 1 g q8h), meropenem (98.2% CFR at 1 g q8h), ertapenem (91.7% CFR at 1 g q24h), piperacillin/ tazobactam (93.7% CFR at 3.375 g q6h), ceftazidime (91.1% CFR at 2 g q8h), and cefepime (92.9% CFR at 1 g q12h and 95.8% CFR at 2 g q12h). Ceftriaxone, ciprofloxacin, and levofloxacin exhibited CFRs < 82%. CONCLUSIONS: Considering contemporary susceptibility data for aerobic bacteria, monotherapy with any of the three carbapenems or piperacillin/tazobactam 3.375 g q6h would provide optimal exposure for the pathogens commonly encountered in secondary peritonitis. Cefepime (in combination with metronidazole to provide anti-anaerobic coverage) also would be an acceptable choice, as would ceftazidime given at 2 g q8h (again in combination with metronidazole). Despite the popularity of combination therapy based on ciprofloxacin, levofloxacin, or ceftriaxone with metronidazole, these choices appear to be inferior to the other options because of emerging antibiotic resistance, particularly in E. coli.

Pharmacodynamic profiling of imipenem, meropenem and ertapenem against clinical isolates of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. from Brazil.

The pharmacodynamic potency of imipenem, meropenem and ertapenem against extended-spectrum beta-lactamase (ESBL)-producing isolates was investigated. Minimal inhibitory concentration (MIC) determination, confirmation of ESBLs by Etest and the disk approximation test were performed for 133 ESBL-producing isolates of Escherichia coli and Klebsiella spp. Pharmacodynamic exposure, measured as percent of the dosing interval during which free drug was above the MIC (% fT>MIC), was modelled via a 5000-subject Monte Carlo simulation. Bactericidal cumulative fraction of response (CFR), defined as 40% fT>MIC, was calculated against each bacterial population. All agents achieved high bactericidal CFR against all ESBL isolates as a group, but ertapenem (96.26%) was slightly less effective than imipenem (99.96%) and meropenem (99.90%) (P<0.05). Similar results were observed against Klebsiella spp. only (P<0.05). Against E. coli, CFRs were close to 100%. Ertapenem is probably an effective agent against ESBL-producing bacteria, although its ability to achieve bactericidal pharmacodynamic exposures will depend on the bacterial susceptibility.