Real-world evaluation of imipenem/cilastatin/relebactam across US medical centres.

We assessed 160 patients who received imipenem/cilastatin/relebactam for ≥2 days. At treatment initiation, the median Charlson Comorbidity Index was 5, 45% were in the intensive care unit, and 19% required vasopressor support. The in-hospital mortality rate was 24%. These data advance our understanding of real-world indications and outcomes of imipenem/cilastatin/relebactam use.

Cost-effectiveness analysis of cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplant recipients from a US payer perspective.

To evaluate the cost-effectiveness of letermovir versus no prophylaxis for the prevention of cytomegalovirus infection and disease in adult cytomegalovirus-seropositive allogeneic hematopoietic cell transplantation (allo-HCT) recipients. A decision model for 100 patients was developed to estimate the probabilities of cytomegalovirus infection, cytomegalovirus disease, various other complications, and death in patients receiving letermovir versus no prophylaxis. The probabilities of clinical outcomes were based on the pivotal phase 3 trial of letermovir use for cytomegalovirus prophylaxis versus placebo in adult cytomegalovirus-seropositive recipients of an allo-HCT. Costs of prophylaxis with letermovir and of each clinical outcome were derived from published sources or the trial clinical study reports. Incremental cost-effectiveness ratios (ICERs) in terms of cost per quality-adjusted life year (QALY) gained were used in the model. One-way and probabilistic sensitivity analyses were conducted to explore uncertainty around the base-case analysis. In this model, the use of letermovir prophylaxis would lead to an increase of QALYs (619) and direct medical cost ($1 733 794) compared with no prophylaxis (578 QALYs; $710 300) in cytomegalovirus-seropositive recipients of an allo-HCT. Letermovir use for cytomegalovirus prophylaxis was a cost-effective option versus no prophylaxis with base-case analysis ICER $25 046/QALY gained. One-way sensitivity analysis showed the most influential parameter was mortality rate. The probabilistic sensitivity analysis showed a 92% probability of letermovir producing an ICER below the commonly accepted willingness-to-pay threshold of $100 000/QALY gained. Based on this model, letermovir use for cytomegalovirus prophylaxis was a cost-effective option in adult cytomegalovirus-seropositive recipients of an allo-HCT.

Pseudomonas infections among hospitalized adults in Latin America: a systematic review and meta-analysis.

BACKGROUND: Treatment of resistant Pseudomonas aeruginosa infection continues to be a challenge in Latin American countries (LATAM). We synthesize the literature on the use of appropriate initial antibiotic therapy (AIAT) and inappropriate initial antibiotic therapy (IIAT) in P. aeruginosa infections, and the literature on risk factors for acquisition of resistant P. aeruginosa among hospitalized adult patients in LATAM. METHODS: MEDLINE, EMBASE, Cochrane, and LILAC were searched between 2000 and August 2019. Abstracts and full-text articles were screened in duplicate. Random effects meta-analysis was conducted when studies were sufficiently similar. RESULTS: The screening of 165 citations identified through literature search yielded 98 full-text articles that were retrieved and assessed for eligibility, and 19 articles conducted in Brazil (14 articles), Colombia (4 articles), and Cuba (1 article) met the inclusion criteria. Of 19 eligible articles, six articles (840 subjects) examined AIAT compared to IIAT in P. aeruginosa infections; 17 articles (3203 total subjects) examined risk factors for acquisition of resistant P. aeruginosa; and four articles evaluated both. Four of 19 articles were rated low risk of bias and the remaining were deemed unclear or high risk of bias. In meta-analysis, AIAT was associated with lower mortality for P. aeruginosa infections (unadjusted summary OR 0.48, 95% CI 0.28-0.81; I2 = 59%), compared to IIAT and the association with mortality persisted in subgroup meta-analysis by low risk of bias (3 articles; unadjusted summary OR 0.46, 95% CI 0.28-0.81; I2 = 0%). No meta-analysis was performed for studies evaluating risk factors for acquisition of resistant P. aeruginosa as they were not sufficiently similar. Significant risk factors for acquisition of resistant P. aeruginosa included: prior use of antibiotics (11 articles), stay in the intensive care unit (ICU) (3 articles), and comorbidity score (3 articles). Outcomes were graded to be of low strength of evidence owing to unclear or high risk of bias and imprecise estimates. CONCLUSION: Our study highlights the association of AIAT with lower mortality and prior use of antibiotics significantly predicts acquiring resistant P. aeruginosa infections. This review reinforces the need for rigorous and structured antimicrobial stewardship programs in the LATAM region.

A Combination Antibiogram Evaluation for Pseudomonas aeruginosa in Respiratory and Blood Sources from Intensive Care Unit (ICU) and Non-ICU Settings in U.S. Hospitals.

Pseudomonas aeruginosa is an important pathogen associated with significant morbidity and mortality. U.S. guidelines for the treatment of hospital-acquired and ventilator-associated pneumonia recommend the use of two antipseudomonal drugs for high-risk patients to ensure that ≥95% of patients receive active empirical therapy. We evaluated the utility of combination antibiograms in identifying optimal anti-P.aeruginosa drug regimens. We conducted a retrospective cross-sectional analysis of the antimicrobial susceptibility of all nonduplicate P.aeruginosa blood and respiratory isolates collected between 1 October 2016 and 30 September 2017 from 304 U.S. hospitals in the BD Insights Research Database. Combination antibiograms were used to determine in vitro rates of susceptibility to potential anti-P.aeruginosa combination regimens consisting of a backbone antibiotic (an extended-spectrum cephalosporin, carbapenem, or piperacillin-tazobactam) plus an aminoglycoside or fluoroquinolone. Single-agent susceptibility rates for the 11,701 nonduplicate P.aeruginosa isolates ranged from 72.7% for fluoroquinolones to 85.0% for piperacillin-tazobactam. Susceptibility rates were higher for blood isolates than for respiratory isolates (P < 0.05). Antibiotic combinations resulted in increased susceptibility rates but did not achieve the goal of 95% antibiotic coverage. Adding an aminoglycoside resulted in higher susceptibility rates than adding a fluoroquinolone; piperacillin-tazobactam plus an aminoglycoside resulted in the highest susceptibility rate (93.3%). Intensive care unit (ICU) isolates generally had lower susceptibility rates than non-ICU isolates. Commonly used antipseudomonal drugs, either alone or in combination, did not achieve 95% coverage against U.S. hospital P.aeruginosa isolates, suggesting that new drugs are needed to attain this goal. Local institutional use of combination antibiograms has the potential to optimize empirical therapy of infections caused by difficult-to-treat pathogens.

Risk factors for hospitalized patients with resistant or multidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis.

Background: Identifying risk factors predicting acquisition of resistant Pseudomonas aeruginosa will aid surveillance and diagnostic initiatives and can be crucial in early and appropriate antibiotic therapy. We conducted a systematic review examining risk factors of acquisition of resistant P. aeruginosa among hospitalized patients. Methods: MEDLINE®, EMBASE®, and Cochrane Central were searched between 2000 and 2016 for studies examining independent risk factors associated with acquisition of resistant P. aeruginosa, among hospitalized patients. Random effects model meta-analysis was conducted when at least three or more studies were sufficiently similar. Results: Of the 54 eligible articles, 28 publications (31studies) examined multi-drug resistant (MDR) or extensively drug resistant (XDR) P. aeruginosa and 26 publications (29 studies) examined resistant P. aeruginosa. The acquisition of MDR P. aeruginosa, as compared with non-MDR P. aeruginosa, was significantly associated with intensive care unit (ICU) admission (3 studies: summary adjusted odds ratio [OR] 2.2) or use of quinolones (4 studies: summary adjusted OR 3.59). Acquisition of MDR or XDR compared with susceptible P. aeruginosa was significantly associated with prior hospital stay (4 studies: summary adjusted OR 1.90), use of quinolones (3 studies: summary adjusted OR 4.34), or use of carbapenems (3 studies: summary adjusted OR 13.68). The acquisition of MDR P. aeruginosa compared with non-P. aeruginosa was significantly associated with prior use of cephalosporins (3 studies: summary adjusted OR 3.96), quinolones (4 studies: summary adjusted OR 2.96), carbapenems (6 studies: summary adjusted OR 2.61), and prior hospital stay (4 studies: summary adjusted OR 1.74). The acquisition of carbapenem-resistant P. aeruginosa compared with susceptible P. aeruginosa, was statistically significantly associated with prior use of piperacillin-tazobactam (3 studies: summary adjusted OR 2.64), vancomycin (3 studies: summary adjusted OR 1.76), and carbapenems (7 studies: summary adjusted OR 4.36). Conclusions: Prior use of antibiotics and prior hospital or ICU stay was the most significant risk factors for acquisition of resistant P. aeruginosa. These findings provide guidance in identifying patients that may be at an elevated risk for a resistant infection and emphasize the importance of antimicrobial stewardship and infection control in hospitals.

Risk factors for Pseudomonas aeruginosa infections in Asia-Pacific and consequences of inappropriate initial antimicrobial therapy: A systematic literature review and meta-analysis.

OBJECTIVES: Treating infections of Gram-negative pathogens, in particular Pseudomonas aeruginosa, is a challenge for clinicians in the Asia-Pacific region owing to inherent and acquired antimicrobial resistance. This systematic review and meta-analysis provides updated information on risk factors for P. aeruginosa infection in Asia-Pacific as well as the consequences (e.g. mortality, costs) of initial inappropriate antimicrobial therapy (IIAT). METHODS: Embase and MEDLINE databases were searched for Asia-Pacific studies reporting the consequences of IIAT versus initial appropriate antimicrobial therapy (IAAT) in Gram-negative bacterial infections as well as risk factors for serious P. aeruginosa infection. A meta-analysis of unadjusted mortality was performed using a random-effects model. RESULTS: A total of 22 studies reporting mortality and 13 reporting risk factors were identified. The meta-analysis demonstrated that mortality was significantly lower in patients receiving IAAT versus IIAT, with a 67% reduction observed for 28- or 30-day all-cause mortality (odds ratio=0.33, 95% confidence interval 0.20-0.55; P<0.001). Risk factors for serious P. aeruginosa infection include previous exposure to antimicrobials, mechanical ventilation and previous hospitalisation. CONCLUSION: High rates of antimicrobial resistance in Asia-Pacific as well as the increased mortality associated with IIAT and the presence of risk factors for serious infection highlight the importance of access to newer and appropriate antimicrobials.

Development and Assessment of Risk Scores for Carbapenem and Extensive ß-Lactam Resistance Among Adult Hospitalized Patients With Pseudomonas aeruginosa Infection.

Importance: Treatment of patients with infections due to Pseudomonas aeruginosa has been complicated by increased antibiotic resistance rates, which contribute to delayed appropriate treatment and deleterious outcomes. Objective: To develop 2 clinical risk scores based on variables available at clinical presentation to estimate the risk of carbapenem resistance (CR) or extensive ß-lactam resistance (EBR) among hospitalized, adult patients with P aeruginosa infections. Design, Setting, and Participants: This retrospective cohort study included adult (age, ≥18 years) members of Kaiser Permanente Southern California (KPSC) with a P aeruginosa infection during hospitalization from September 1, 2011, through August 31, 2016, who received antibiotic therapy within 2 days of the culture date. Data were analyzed from July 2, 2017, through August 15, 2018. Exposures: Demographic, clinical, and laboratory covariates 1 year before the index culture date were evaluated. Main Outcomes and Measures: Pseudomonas aeruginosa was categorized as antibiotic susceptible, CR, or EBR (nonsusceptibility to carbapenems, ceftazidime, and combined piperacillin sodium and tazobactam sodium). Patients were randomly split (1:1) into training and validation data sets. The training data set was used to develop 2 prediction models using high-performance logistic regression with variable selection by Schwarz-Bayesian criterion. The models were translated into risk scores, with risk score points equaling the weighted sums of regression coefficients from the prediction model. The patient's risk was estimated as the inverse logit of the risk score. Results: Of the 7775 patients with 11 502 P aeruginosa infections included in the analysis, most were male (4308 [55.4%]) and non-Hispanic white (3927 [50.5%]). The mean (SD) age was 70.3 (15.5) years. Among 11 502 P aeruginosa infections, 2324 (20.2%) were CR, 9178 (79.8%) were non-CR, 1033 (9.0%) were EBR, and 10 469 were non-EBR (91.0%). The strongest predictors of resistance in the CR and EBR models were history of CR P aeruginosa infection (odds ratios [ORs], 8.80 [95% CI, 6.74-11.49] and 5.04 [95% CI, 3.88-6.54], respectively), tracheostomy (ORs, 3.49 [95% CI, 2.92-4.16] and 3.13 [95% CI, 2.50-3.91], respectively), and carbapenem use in the prior 30 days (ORs, 4.18 [95% CI, 3.29-5.31] and 2.26 [95% CI, 1.74-2.93], respectively). The models for CR and EBR performed well, with areas under the receiver operating characteristics curve of 0.81 or greater for the training and validation data sets. Conclusions and Relevance: The findings of this study suggest that parsimonious risk scores can aid physicians in appropriate treatment selection during the critical period when P aeruginosa infection is suspected but antibiotic susceptibility results are not yet available.

Cost-effectiveness of ceftolozane/tazobactam plus metronidazole compared with piperacillin/tazobactam as empiric therapy for the treatment of complicated intra-abdominal infections based on the in-vitro surveillance of bacterial isolates in the UK.

AIMS: An increase in the prevalence of antimicrobial resistance among gram-negative pathogens has been noted recently. A challenge in empiric treatment of complicated intra-abdominal infection (cIAI) is identifying initial appropriate antibiotic therapy, which is associated with reduced length of stay and mortality compared with inappropriate therapy. The objective of this study was to assess the cost-effectiveness of ceftolozane/tazobactam + metronidazole compared with piperacillin/tazobactam (commonly used in this indication) in the treatment of patients with cIAI in UK hospitals. METHODS: A decision-analytic Monte Carlo simulation model was used to compare costs (antibiotic and hospitalization costs) and quality-adjusted life years (QALYs) of patients infected with gram-negative cIAI and treated empirically with either ceftolozane/tazobactam + metronidazole or piperacillin/tazobactam. Bacterial isolates were randomly drawn from the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) database, a surveillance database of non-duplicate bacterial isolates collected from patients in the UK infected with gram-negative pathogens. Susceptibility to initial empiric therapy was based on the measured susceptibilities reported in the PACTS database. RESULTS: Ceftolozane/tazobactam + metronidazole was cost-effective when compared with piperacillin/tazobactam, with an incremental cost-effectiveness ratio (ICER) of £4,350/QALY and 0.36 hospitalization days/patient saved. Costs in the ceftolozane/tazobactam + metronidazole arm were £2,576/patient, compared with £2,168/patient in the piperacillin/tazobactam arm. The ceftolozane/tazobactam + metronidazole arm experienced a greater number of QALYs than the piperacillin/tazobactam arm (14.31/patient vs 14.21/patient, respectively). Ceftolozane/tazobactam + metronidazole remained cost-effective in one-way sensitivity and probabilistic sensitivity analyses. CONCLUSIONS: Economic models can help to identify the appropriate choice of empiric therapy for the treatment of cIAI. Results indicated that empiric use of ceftolozane/tazobactam + metronidazole is cost-effective vs piperacillin/tazobactam in UK patients with cIAI at risk of resistant infection. This will be valuable to commissioners and clinicians to aid decision-making on the targeting of resources for appropriate antibiotic therapy under the premise of antimicrobial stewardship.

Diabetic peripheral neuropathy: resource utilization and burden of illness.

INTRODUCTION: Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes and accounts for significant morbidity by pre-disposing the foot to ulceration and lower extremity amputation. Using a large US commercial claims database, this study analyzes the drug class usage and co-morbidities associated with DPN as well as estimates the associated economic burden. METHODS: Patients older than 18 and diagnosed with DPN were followed longitudinally for 2 years pre- and post-diagnosis date. Patients were analyzed for age, gender, hospital visits, ER and doctor's office visits, pharmacy claims, co-morbidities, and drug classes prescribed pre- and post-DPN diagnosis. The economic impact post-diagnosis of DPN was compared to the patients' pre-diagnosis resource use. RESULTS: In total, 10,982 incident DPN patients were identified, with a median age of 61 years, and an equal gender distribution. Post-DPN diagnosis, there was a 20% increase in the number of patients visiting hospitals and a 46% increase in the number of visits to hospitals. Further, there was a 46% increase in the annual cost per patient associated with visits to the hospitals, emergency room (ER), doctor's office, and pharmacy claims. As per the analysis presented in this study, increase in the number of visits, cost per visit, and number of patients visiting hospitals, ER and doctor's offices added up to a 46% increase in aggregated cost associated with Medical Resource Utilization (MRU) owing to DPN, with the highest increase (60%) in costs associated with hospitalization of patients with DPN. CONCLUSION: This study highlights the high economic burden associated with DPN. The results indicate that resource use significantly increases post-diagnosis of DPN, which leads to an increase in costs for payers. A noticeable proportion of patients with DPN had a pain co-diagnosis signifying the need for treatments that can effectively manage painful DPN.

The prevalence and economic impact of prescription opioid-related side effects among patients with chronic noncancer pain.

OBJECTIVES: To estimate the prevalence of opioid-related side effects among patients with chronic noncancer pain (CNCP) who initiated opioids and compare healthcare costs of patients with and without side effects using patient survey, medical charts, and claims data. PATIENTS, PARTICIPANTS: Patients initiating opioids, who were aged ≥18 years, had ≥1 pain diagnosis, and did not have cancer, were identified through claims data and medical records from a Central Massachusetts medical group practice and mailed surveys between October 2010 and July 2012. MAIN OUTCOMES MEASURES: Prevalence of opioid-related side effects was estimated from patient surveys, charts, and claims data within 90 days after opioid initiation (study period). Study period healthcare costs were compared between patients with and without side effects (self-reported problematic side effects or side effects recorded in medical charts or claims). RESULTS: Among patients with CNCP who initiated opioids and completed the survey (N = 167), the average age was 53 years, and 62.9 percent were women. Based on the survey, charts, and claims, 91.6 percent, 15.0 percent, and 19.2 percent of patients, respectively, had ≥1 opioid-related side effect. Overall, 59.3 percent of patients reported having ≥1 problematic side effect or side effect recorded in charts or claims. In the analysis that controlled for baseline characteristics and resource use, patients with versus without side effects had higher mean study period healthcare costs ($3,347 vs $2,521, p = 0.049). CONCLUSIONS: Prevalence of opioid-related side effects among patients with CNCP who initiated opioids was substantially higher based on patient survey than from charts or claims. Opioid-related side effects were associated with significantly higher healthcare costs.

Composite measure to assess efficacy/gastrointestinal tolerability of tapentadol ER versus oxycodone CR for chronic pain: pooled analysis of randomized studies.

OBJECTIVE: To evaluate a composite measure for chronic pain that balances pain relief with tolerability. DESIGN: Post hoc meta-analysis of three randomized, multicenter, double-blind studies. PARTICIPANTS: Subjects with moderate-to-severe chronic osteoarthritis knee pain or low back pain who had been randomized to receive active treatment with tapentadol extended release (ER; n = 978) or oxycodone controlled release (CR; n = 999). Twenty-two subjects were excluded, mainly because they did not receive treatment. MAIN OUTCOME MEASURES: We defined the composite measure as ≥30 percent pain relief without nausea/vomiting/constipation and without discontinuations (≥30 percent PRT [pain relief/tolerability]). We also considered ≥50 percent PRT as well as ≥30 percent and ≥50 percent pain relief without any adverse events of any type. To further evaluate ≥30 percent PRT, we studied its relationship with four patient-reported outcomes: EQ-5D, Physical and Mental Component Summaries of SF-36, Patient Global Impression of Change, and Patient Assessment of Constipation Symptoms. RESULTS: At week 12, tapentadol ER recipients were more likely to have ≥30 percent PRT than oxycodone CR recipients (OR, 3.15; 95% CI, 2.47, 4.00; p < 0.001). Significant differences were also observed with the other three composite measures (p < 0.001). At week 12, subjects with ≥30 percent PRT had more favorable changes in all patient-reported outcomes than those without and were more likely to have threshold changes in EQ-5D and SF-36 (all p < 0.001). CONCLUSIONS: Tapentadol ER was associated with significantly better composite outcomes than oxycodone CR. Because both pain relief and gastrointestinal tolerability appeared to be related to outcomes, the composite measure may represent a useful tool for comparing opioids that merits further evaluation.

Budget impact analysis of tapentadol extended release for the treatment of moderate to severe chronic noncancer pain.

BACKGROUND: Opioids are commonly used to manage chronic pain. Although traditional µ-opioids are effective in reducing pain, they are often associated with opioid-induced side effects (OISEs) that can limit treatment effectiveness. Studies have shown that tapentadol extended release (ER) has a lower incidence of gastrointestinal adverse events than oxycodone controlled release (CR) at equianalgesic doses. OBJECTIVE: A model was developed to estimate the budget impact of placing tapentadol ER on a hypothetical US health plan formulary of Schedule II long-acting opioids. METHODS: We estimated annual direct health care costs for patients who received 6-month therapy with long-acting formulations of tapentadol, oxycodone, morphine, hydromorphone, oxymorphone, or fentanyl. Costs included medications, copayments, OISE management, and switching/discontinuation. Published estimates of incidence/prevalence, OISEs, and pain management resources and costs were used. The base case analysis assumed a 10% formulary share of tapentadol ER with a 10% decrease of oxycodone CR. The resulting per-member per-month (PMPM) formulary cost differences and results of a 1-way sensitivity analysis are reported. RESULTS: In a health plan of 500,000 members, 2600 (0.52%) are estimated to experience chronic pain annually. Adding tapentadol ER to the formulary was associated with an annual budget savings of $148,945 ($0.0248 PMPM). This savings was achieved through a decrease in both pharmacy costs ($144,062; $0.0240 PMPM) and medical costs ($4883; $0.0008 PMPM). Cost decreases were driven by lower daily average consumption and fewer OISEs with tapentadol ER versus oxycodone CR, leading to reduced resource utilization over 6 months of treatment. Sensitivity analyses showed results were most sensitive to drug acquisition costs. CONCLUSIONS: Our results suggest that replacing 10% of oxycodone CR's formulary share with tapentadol ER would decrease the overall budget of a health plan with 500,000 members. Placing tapentadol ER on a health plan formulary may result in a reduction in both pharmacy and medical costs.

Clinical simulation model of long-acting opioids for treatment of chronic non-cancer pain in the United States.

OBJECTIVE: To evaluate costs and outcomes associated with initial tapentadol ER vs oxycodone CR for the treatment of chronic non-cancer pain (CNCP) in the US. METHODS: This study developed a Monte-Carlo simulation based on the scientific foundation established by published models of long-acting opioids (LAO) in patients having moderate-to-severe CNCP. It estimates costs and outcomes associated with the use of tapentadol ER vs oxycodone CR over a 1-year period from the perspective of a US payer. LAO effectiveness and treatment-emergent adverse event (TEAE) rates are derived from clinical trials of tapentadol ER vs oxycodone CR; other inputs are based on published literature supplemented sparingly with clinical opinion. Sensitivity analyses consider the impact of real-world dosing patterns for LAO on treatment costs. RESULTS: Initial tapentadol ER consistently demonstrates better outcomes than initial oxycodone CR (proportion of patients achieving adequate pain relief and no GI TEAE; acute TEAE-free days; days free of chronic constipation; quality-adjusted life days; productive working hours). While total costs with initial tapentadol ER are slightly (2.2%) higher than with initial oxycodone CR, nearly twice as many modeled patients in the initial tapentadol ER arm (29% vs 15%) achieve adequate pain relief and no GI TEAE compared to initial oxycodone CR. In sensitivity analyses, tapentadol ER becomes a dominant strategy when real-world dosing patterns are considered. CONCLUSION: The additional costs to produce better outcomes (pain relief and no GI TEAE) associated with tapentadol ER are small in the context of double the likelihood of a patient response with tapentadol ER. When daily average consumption (DACON) for oxycodone CR is factored into the analysis, initial tapentadol ER becomes a dominant strategy. Our findings are both strengthened, and limited by the use of randomized trial-centric input parameters. These results should be validated as inputs from clinical practice settings become available.

Severity assessment of skin and soft tissue infections: cohort study of management and outcomes for hospitalized patients.

BACKGROUND: Skin and soft tissue infections (SSTIs) are caused by bacterial invasion of the skin and underlying soft tissues and can present with a wide spectrum of signs, symptoms and illness severity. They are a common indication for antimicrobial therapy. However, there are few data on treatment outcomes or the validity of clinical severity scores. METHODS: Two hundred and five adult patients admitted to Ninewells Hospital, Scotland in 2005, and treated with antibiotics for SSTI, were identified. They were stratified into four classes of severity (class IV = most severe) based on sepsis, co-morbidity and their standardized early warning score (SEWS). Empirical antimicrobial therapy by severity class was compared with the recommendations of a UK guideline. RESULTS: Thirty-five different empirical antimicrobial regimens were prescribed. Overall, 43% of patients were over-treated, this being particularly common in the lowest severity class I (65% patients). Thirty-day mortality was 9% (18/205) and 17 patients (8%) died during their index admission. Mortality (30 day) and inadequate therapy increased with severity class: I, no sepsis or co-morbidity (45% patients, 1% mortality, 14% therapy inadequate); II, significant co-morbidity but no sepsis (32% patients, 11% mortality, 39% therapy inadequate); III, sepsis but SEWS <4 (17% of patients, 17% mortality, 39% therapy inadequate); and IV, sepsis plus SEWS ≥ 4 (6% of patients, 33% mortality, 92% therapy inadequate). CONCLUSIONS: SSTI in hospital is associated with significant mortality. Choice of empirical therapy is not evidence based, with significant under-treatment of severely ill patients.

Outcomes and management costs in patients hospitalized for skin and skin-structure infections.

BACKGROUND: This study was conducted to determine outcomes and costs of treating complicated skin and skin-structure infections (cSSSIs) due to gram-positive only, gram-negative only, or mixed pathogens (gram-positive and gram-negative), including those with methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa. METHODS: Data on length of stay (LOS), mortality, and charges for cSSSIs were compiled from claims in the multihospital Solucient database from 2002 to 2006. RESULTS: Among the 5156 cases with pathogens identified, 59.7% were gram-positive, 21.5% were gram-negative, and 18.8% were mixed. Patients with mixed pathogens incurred significantly higher LOS (17.2 days), mortality (10.2%), and charges ($80,093) than those with cSSSIs due to gram-negative pathogens (10.1 days, 6.5%, and $41,634, respectively) or to gram-positive pathogens (9.5 days, 4.8%, and $40,046, respectively). MRSA was isolated from 21.6% of all cases and from 26.3% of cases involving mixed pathogens. MRSA cases had significantly longer LOS and greater mortality than non-MRSA cases, but similar total charges. P aeruginosa occurred in 13.3% of all cases and in 36.3% of cases involving mixed pathogens. P aeruginosa cases had significantly higher LOS and charges compared with non‒P aeruginosa cases. CONCLUSION: Although gram-positive pathogens were the most common causes of cSSSIs, cases involving mixed and resistant pathogens were associated with longer LOS, greater mortality, and higher total charges.

Medical resource utilization among patients with ventilator-associated pneumonia: pooled analysis of randomized studies of doripenem versus comparators.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is associated with increased medical resource utilization, but few randomized studies have been conducted to evaluate the effect of initial antibiotic therapy. To assess medical resource utilization in patients with VAP, we conducted a pooled analysis of two prospective, randomized, open-label, multicenter, phase III studies, which also showed that doripenem was clinically noninferior to comparators. METHODS: We assessed durations of mechanical ventilation, intensive care unit (ICU) stay, and hospitalization in patients with VAP who received at least 1 dose of doripenem or a comparator in the phase III studies. Comparators were piperacillin/tazobactam (study 1) and imipenem (study 2). We analyzed between-group differences in medical resource utilization endpoints by comparison of Kaplan-Meier curves with generalized Wilcoxon test and in microbiologic eradication rates by two-sided Fisher's exact test. RESULTS: 625 patients with VAP were evaluated and received at least 1 dose of doripenem (n = 312) or a comparator (n = 313). Median durations of mechanical ventilation (7 versus 10 days; P = 0.008) and hospitalization (22 versus 26 days; P = 0.010) were shorter for doripenem than comparators; corresponding ICU stays were 12 and 13 days (P = 0.065). All-cause, overall mortality rates were similar (51/312 [16%] versus 47/313 [15%]; P = 0.648). MIC90 values against Pseudomonas aeruginosa for doripenem versus imipenem were 4 versus 16 microg/mL in study 2. P. aeruginosa was eradicated from 16/24 (67%) doripenem recipients and 10/24 (42%) comparator recipients (P = 0.147). In patients with P. aeruginosa at baseline, median durations of mechanical ventilation (7 versus 13 days; P = 0.031) and ICU stay (13 versus 21 days; P = 0.027) were shorter for doripenem; corresponding hospital stays were 24 and 35 days (P = 0.129). CONCLUSIONS: Doripenem was associated with lower medical resource utilization than comparators. Differences in antipseudomonal activity may have contributed to these findings. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00211003 (study 1) and NCT00211016 (study 2).

Economic assessment of doripenem versus imipenem in the treatment of ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP), the most common nosocomial infection in critically ill patients, is associated with significantly longer duration of mechanical ventilation, and increased mortality, hospital days, and health-care costs. A previously published prospective, randomized study established the noninferiority of intravenous (IV) doripenem versus IV imipenem/cilastatin ('imipenem') for VAP. This study compares the economic outcomes of IV therapy with doripenem versus imipenem as first-line treatment for VAP. METHODS: A decision-analytic model of inpatient care and outcomes for VAP was used to estimate costs associated with VAP treatment. The model calculates total hospital costs, comprising costs of initial and concomitant therapy, and costs associated with mechanical ventilation, intensive care unit stays, and total days in hospital. RESULTS: Total treatment costs for doripenem were $10,630 lower than for imipenem ($71,259 vs. 81,889), driven primarily by differences in costs of mechanical ventilation ($45,224 for doripenem, $57,348 for imipenem). Probabilistic sensitivity analyses found doripenem consistently cost saving versus imipenem in 1,000 simulations. Study limitations include use of a simple model to represent a complex disease process and reliance on trial data that may not reflect real-world care and outcomes. CONCLUSIONS: Doripenem is a cost saving first-line treatment for VAP versus imipenem while providing an equivalent rate of cure.

Economic evaluation of doripenem for the treatment of nosocomial pneumonia in the US: discrete event simulation.

OBJECTIVE: Patients with nosocomial pneumonia, particularly associated with ventilator use, are at an increased risk of death and further morbidity. Doripenem is a new broad-spectrum carbapenem that is approved for complicated intra-abdominal infection and complicated urinary tract infection and is under the Food and Drug Administration (FDA)'s review for nosocomial pneumonia and ventilator-associated pneumonia in the United States (US). The economic implications of this new antibiotic, relative to imipenem for treatment of nosocomial pneumonia, were investigated. RESEARCH DESIGN AND METHODS: An economic model of the clinical course of nosocomial pneumonia after initiation of treatment was developed using discrete event simulation. Pairs of identical patients are generated; one receives doripenem and the other receives imipenem. Their clinical course is simulated using clinical trial data on treatment response, seizure rates, mortality, length of hospital and intensive care unit stays, days on mechanical ventilation, and emerging Pseudomonas aeruginosa (PsA) resistance; published treatment and hospital costs; and PsA transmission risk. Analyses of 10,000 patients per treatment for 100 replications were performed. From the perspective of a comprehensive payer, costs - in 2007 US Dollars (USDs) - were estimated for a treatment episode (35-49 days) without discounting. Study limitation includes clinical trial-driven design of the model in which some aspects may not represent actual practice; some assumptions around efficacy data due to data unavailability; and lack of consideration of factors that impact disease transmission such as hospital environment, hospital size, and hospital infection control as these analyses were not intended for any specific healthcare institution. RESULTS: Doripenem yielded an average of approximately $7000 in savings per patient compared to imipenem, with 95% driven by reduction in hospital length of stay. The model predicted 63% fewer seizures, 52% fewer emerging PsA resistance, and 15% shorter stays leading to 46% fewer transmissions associated with doripenem. CONCLUSION: Using doripenem for treatment of nosocomial pneumonia is expected to yield significant savings compared to imipenem use in the US.

Outcomes associated with initial versus later vancomycin use in patients with complicated skin and skin-structure infections.

BACKGROUND: Delayed coverage of pathogens including meticillin-resistant Staphylococcus aureus (MRSA) in pneumonia and bacteraemia has been associated with increased mortality and length of hospital stay (LOS). However, less is known about the impact of delayed appropriate coverage in complicated skin and skin-structure infections (cSSSIs). OBJECTIVE: To evaluate the clinical and economic outcomes associated with early versus late use of vancomycin in the management of patients hospitalized for cSSSIs. METHODS: Retrospective analysis was performed using an inpatient claims database of >500 US hospitals in 2005. Using prescription claims, patients with primary or secondary cSSSI admissions were classified into three groups: 1 = early vancomycin monotherapy; 2 = early vancomycin combination therapy; 3 = late vancomycin therapy. Outcomes studied included LOS and inpatient hospital costs. One-way analysis of variance was used for unadjusted analysis and multivariate regression methods were used to control for co-variates. RESULTS: A total of 34,942 patients (27.78% of all patients with cSSSIs) were treated with vancomycin. Mean age was 54.7 years and 54.3% of the patients were males. Mean unadjusted total LOS was 8.46, 9.44 and 13.2 days, and hospital costs in 2005 values were USD10 211.94, USD12 361.94 and USD18 344.00 for groups 1, 2 and 3, respectively. In-hospital mortality rate was highest in group 3 (4.18%) and lowest in group 1 (1.75%). Generalized linear models used to control for potential confounding variables between early versus late vancomycin use suggest that among cSSSI patients late vancomycin use is an independent predictor of higher LOS and costs. CONCLUSION: In this large inpatient database, later vancomycin use in patients with cSSSIs appears to be significantly associated with higher LOS and total costs.

Hospital resource utilization with doripenem versus imipenem in the treatment of ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a common nosocomial infection that is associated with prolonged length of stay (LOS) and significant mortality. OBJECTIVE: The aim of this study was to compare resource utilization with doripenem, an investigational carbapenem, versus imipenem from a hospital perspective among patients with VAP. METHODS: This analysis was based on data from a Phase III, randomized, open-label, noninferiority study that compared clinical cure of VAP with doripenem 500 mg q8h i.v. (4-hour infusion) with imipenem 500 mg q6h (30-minute infusion) or 1000 mg q8h i.v. (1-hour infusion). Total hospital LOS, intensive care unit (ICU) LOS, and time on mechanical ventilation for doripenem and imipenem were compared in a clinical modified intent-to-treat population. P values were determined using the generalized Wilcoxon test, which compared treatments in a time-to-event analysis, censoring patients at the late follow-up visit (28-35 days after the end of i.v. therapy). RESULTS: Patients in the doripenem and imipenem groups had similar baseline clinical characteristics. Median hospital LOS was significantly shorter with doripenem versus imipenem (22 vs 27 days; P=0.010); median time on mechanical ventilation was significantly shorter for doripenem (7 vs 10 days; P=0.034); median ICU LOSs were similar between the 2 groups (12 vs 13 days). Clinical cure and mortality rates were similar. CONCLUSIONS: Of the 3 primary end points in this analysis, hospital LOS and time on mechanical ventilation were significantly shorter with doripenem compared with imipenem; no statistical significance was observed in ICU LOS. These findings suggest that doripenem use may be associated with an economic and clinical benefit to patients and hospitals.