Invited Commentary: Achieving Post-Bypass Hemostasis in Young Children: At What Cost?

Young children requiring bypass often develop coagulopathy resulting in major postoperative blood loss. Increased post-bypass bleeding and donor exposures are independently associated with adverse outcomes. When transfusion of hemostatic blood products fails to reduce bleeding to an acceptable level, rescue therapies including prothrombin complex concentrates (PCCs), and/or recombinant activated factor VII are being given "off-label" with increasing frequency. A number of studies attempting to determine the safety and efficacy of PCCs in neonates and young children are being published. These studies are most commonly retrospective, observational, performed in a single center with varying doses, indications for, and timing of administration in a small number of patients with varying results. The results of these individual studies are questionable and are not to be generalized to other center's patients. Because factor VIII inhibitor bypassing activity (FEIBA) contains the activated form of factor VII and factor X there are concerns regarding the potential for thrombotic events in a population with a known risk of postoperative thromboembolism. Currently, there is no validated assay with which to measure the efficacy of FEIBA in vivo to determine dose titration. Well-designed multicenter randomized control trials are needed to determine the optimal dose and risk-benefit of PCCs after pediatric cardiac surgery. Until such data are available the decision to give a procoagulant to neonates and young children after bypass needs to be made when the consequences of blood loss and replacement pose more risk than the risk of thrombotic complications from the drug.

Sex differences in sequelae from COVID-19 infection and in long COVID syndrome: a review.

OBJECTIVE: We conducted literature reviews to uncover differential effects of sex on sequelae from coronavirus disease 2019 (COVID-19) and on long COVID syndrome. METHODS: Two authors independently searched OvidSP in Embase, Medline, Biosis, and Derwent Drug File. Publications reporting original, sex-disaggregated data for sequelae of COVID-19 (published before August 2020) and long COVID syndrome (published before June 2021) were included in the reviews. The association between COVID-19 sequelae (i.e. lasting <4 weeks after symptom onset) and sex, and between long COVID syndrome (i.e. lasting >4 weeks after symptom onset) and sex, was determined by odds ratio (OR) and 95% confidence interval (CI) (statistical significance defined by 95% CI not including 1). RESULTS: Of 4346 publications identified, 23 and 12 met eligibility criteria for COVID-19 sequelae and long COVID syndrome, respectively. COVID-19 sequelae in the categories of psychiatric/mood (OR = 1.80; 95% CI: 1.35-2.41), ENT (OR = 1.42; 95% CI: 1.39-1.46), musculoskeletal (OR = 1.15; 95% CI: 1.14-1.16), and respiratory (OR = 1.09; 95% CI: 1.08-1.11) were significantly more likely among females (vs. males), whereas renal sequelae (OR = 0.83; 95% CI: 0.75-0.93) were significantly more likely among males. The likelihood of having long COVID syndrome was significantly greater among females (OR = 1.22; 95% CI: 1.13-1.32), with the odds of ENT (OR = 2.28; 95% CI: 1.94-2.67), GI (OR = 1.60; 95% CI: 1.04-2.44), psychiatric/mood (OR = 1.58; 95% CI: 1.37-1.82), neurological (OR = 1.30; 95% CI: 1.03-1.63), dermatological (OR = 1.29; 95% CI: 1.05-1.58), and other (OR = 1.36; 95% CI: 1.25-1.49) disorders significantly higher among females and the odds of endocrine (OR = 0.75; 95% CI: 0.69-0.81) and renal disorders (OR = 0.74; 95% CI: 0.64-0.86) significantly higher among males. CONCLUSIONS: Sex-disaggregated differences for COVID-19 sequelae and long COVID syndrome were observed. Few COVID-19 studies report sex-disaggregated data, underscoring the need for further sex-based research/reporting of COVID-19 disease.

Interest in Home Birth During the COVID-19 Pandemic: Analysis of Google Trends Data.

INTRODUCTION: Nearly all (94%-99%) pregnant persons in developed countries search for pregnancy-related information online. The advent of the novel coronavirus disease 2019 (COVID-19) and the associated restrictions in hospital policies may have pushed pregnant persons in the United States to consider giving birth at home to achieve their desired birth experience. METHODS: Google Trends is an open, rich source of real-time, anonymized, relative data on disease patterns and population behavior that provides data in the form of search volume index (SVI): the search volume for a queried term relative to overall search volume for a given time frame and geographic location. The SVI is normalized to a scale of 0 to 100. After the World Health Organization declared COVID-19 a pandemic on March 11, 2020, Google Trends was queried on February 21, 2021, for the search term home birth with location set to the United States and the time frame March 11, 2019 to February 21, 2021. RESULTS: The median SVI for home birth during nominally pre-COVID-19 baseline (weeks of March 17, 2019 to March 8, 2020) was relatively constant at 43 (range, 25-56) and increased sharply to 77 during the week of March 15, to 86 during the week of March 22, and peaked at 100 during the week of March 29, 2020. The SVI declined substantially in the following weeks but remained significantly elevated compared with baseline levels. During the approximate 2-year period of query, the states with the highest SVI values (≥80) were Arkansas, Washington, Montana, and Georgia. DISCUSSION: Interest in home birth spiked in the United States immediately after COVID-19 was declared a pandemic and remained significantly elevated thereafter. These results have implications for caregivers and health systems to ensure safe pregnancies and childbirths through the resolution of the ongoing pandemic.

Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials.

The objective of this analysis was to determine if there are sex differences with esketamine for treatment-resistant depression (TRD). Post hoc analyses of three randomized, controlled studies of esketamine in patients with TRD (TRANSFORM-1, TRANSFORM-2 [18-64 years], TRANSFORM-3 [≥ 65 years]) were performed. In each 4-week study, adults with TRD were randomized to esketamine or placebo nasal spray, each with a newly initiated oral antidepressant. Change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was assessed by sex in pooled data from TRANSFORM-1/TRANSFORM-2 and separately in data from TRANSFORM-3 using a mixed-effects model for repeated measures. Use of hormonal therapy was assessed in all women, and menopausal status was assessed in women in TRANSFORM-1/TRANSFORM-2. Altogether, 702 adults (464 women) received ≥ 1 dose of intranasal study drug and antidepressant. Mean MADRS total score (SD) decreased from baseline to day 28, more so among patients treated with esketamine/antidepressant vs. antidepressant/placebo in both women and men: TRANSFORM-1/TRANSFORM-2 women-esketamine/antidepressant -20.3 (13.19) vs. antidepressant/placebo -15.8 (14.67), men-esketamine/antidepressant -18.3 (14.08) vs. antidepressant/placebo -16.0 (14.30); TRANSFORM-3 women-esketamine/antidepressant -9.9 (13.34) vs. antidepressant/placebo -6.9 (9.65), men-esketamine/antidepressant -10.3 (11.96) vs. antidepressant/placebo -5.5 (7.64). There was no significant sex effect or treatment-by-sex interaction (p > 0.35). The most common adverse events in esketamine-treated patients were nausea, dissociation, dizziness, and vertigo, each reported at a rate higher in women than men. The analyses support antidepressant efficacy and overall safety of esketamine nasal spray are similar between women and men with TRD. The TRANSFORM studies are registered at clinicaltrials.gov (identifiers: NCT02417064 (first posted 15 April 2015; last updated 4 May 2020), NCT02418585 (first posted 16 April 2015; last updated 2 June 2020), and NCT02422186 (first posted 21 April 2015; last updated 29 September 2021)).

Treatment resistant depression in women with peripartum depression.

BACKGROUND: Peripartum depression is a leading cause of disease burden for women and yet there is little evidence as to how often peripartum depression does not respond to treatment and becomes treatment resistant depression. We sought to determine the incidence of treatment resistant depression (TRD) in women with peripartum depression. METHODS: Population based retrospective cohort study using a large US claims database. Peripartum depression was defined as having a depression diagnosis during pregnancy or up to 6 months after the end of pregnancy. We included women with prevalent or incident depression. The outcome was the development of TRD within 1 year after the diagnosis of peripartum depression. TRD was defined as having 3 distinct antidepressants or 1 antidepressant and 1 antipsychotic in 1 year. Women with peripartum depression may not be exposed to pharmacological treatments early in pregnancy, therefore we created two groups: 1. women with peripartum depression, and 2. women with peripartum depression diagnosed 3 months before a live birth delivery or within 6 months after that delivery. RESULTS: There were 3,207,684 pregnant women, of whom 2.5% had peripartum depression. Of these women half had incident depression during pregnancy. Five percent of women with peripartum depression developed TRD within 1 year of the depression diagnosis. The risk of developing TRD was 50% higher in women with prevalent depression than in women with incident peripartum depression (P < 0.0001). Results were similar in women with peripartum depression diagnosed later in their pregnancy. Women who went on to develop TRD had more substance use disorders, anxiety, insomnia and painful conditions. CONCLUSIONS: TRD occurs in approximately 5% of women with peripartum depression. The risk of TRD is higher in pregnant women with a history of depression. Women who went on to develop TRD had more psychiatric comorbidities and painful conditions than women who did not.

A Randomized Trial of Off-Site Collaborative Care for Depression in Chronic Hepatitis C Virus.

OBJECTIVE: To test the effectiveness of a collaborative depression care model in improving depression and hepatitis C virus (HCV) care. DATA SOURCES/STUDY SETTING: Hepatitis C virus clinic patients who screened positive for depression at four Veterans Affairs Hospitals. STUDY DESIGN: We compared off-site depression collaborative care (delivered by depression care manager, pharmacist, and psychiatrist) with usual care in a randomized trial. Primary depression outcomes were treatment response (≥50 percent decrease in 20-item Hopkins Symptoms Checklist [SCL-20] score), remission (mean SCL-20 score, <0.5), and depression-free days (DFDs). Primary HCV outcome was receipt of HCV treatment. DATA COLLECTION: Patient data were collected by self-report telephone surveys at baseline and 12 months, and from electronic medical records. PRINCIPAL FINDINGS: Baseline screening identified 292 HCV-infected patients with depression, and 242 patients completed 12-month follow-up (82.9 percent). Intervention participants were more likely to report depression treatment response, remission, and more DFDs than usual care participants. Intervention participants were more likely to receive antiviral treatment; however, the difference was not statistically significant. CONCLUSION: Off-site depression collaborative care improved depression outcomes in HCV patients and may serve as a model for collaboration between mental health and specialty physical health providers in other high co-occurring conditions.

Collaborative Care for Depression in Chronic Hepatitis C Clinics.

OBJECTIVE: Depression is highly prevalent yet underdiagnosed and undertreated among patients with chronic hepatitis C virus (HCV) infection. Collaborative care models have improved depression outcomes in primary care settings, and this study aimed to provide more information on testing such methods in specialty HCV care. METHODS: Hepatitis C Translating Initiatives for Depression Into Effective Solutions (HEPTIDES) was a randomized controlled trial that tested a collaborative depression care model in HCV clinics at four Veterans Affairs facilities. The HEPTIDES intervention consisted of an offsite depression care team (depression care manager, pharmacist, and psychiatrist) that delivered collaborative care. Participant interview data were collected at baseline and at six months. The outcome was depression severity measured with the Hopkins Symptom Checklist (SCL-20) and reported as treatment response (≥50% decrease in SCL-20 item score), remission (mean SCL-20 item score <.5), and depression-free days (DFDs). RESULTS: Baseline screening identified 263 HCV-infected patients with depression. In unadjusted analyses, intervention participants' reports trended toward more treatment response (19% versus 13%) and remission (12% versus 6%), but total number of DFDs (50.9) was similar to that of usual care participants (50.7). These trends did not reach statistical significance for the overall sample in the adjusted analyses: response (odds ratio [OR]=2.02, 95% confidence interval [CI]=.98-4.20), remission (OR=2.63, CI=1.00-6.94), and DFDs (ß=7.6 days, CI=-.99 to 16.2). However, the intervention was effective in improving all three outcomes for patients who did not meet criteria for remission at baseline (SCL-20 score >.5, N=245). CONCLUSIONS: Depression collaborative care resulted in modest improvements in HCV patient depression outcomes. Future research should investigate intervention modifications to improve outcomes in specialty HCV clinics.

Comparison of the bacterial etiology of early-onset and late-onset ventilator-associated pneumonia in subjects enrolled in 2 large clinical studies.

BACKGROUND: Ventilator-associated pneumonia (VAP) is classified as early-onset or late-onset, in part, to identify subjects at risk for infection with resistant pathogens. We assessed differences in the bacterial etiology of early-onset versus late-onset VAP. METHODS: Subjects enrolled in 2004-2006 in 2 clinical studies of doripenem versus imipenem or piperacillin/tazobactam, with a diagnosis of VAP (n = 500) were included in the analysis. Subjects were classified by ventilator status: early-onset VAP (< 5 d of ventilation) or late-onset VAP (≥ 5 d of ventilation). Baseline demographics and bacterial etiology were analyzed by VAP status. RESULTS: Late-onset VAP subjects had higher Acute Physiology and Chronic Health Evaluation (APACHE II) scores (mean 16.6 versus 15.5, P = .008). There were no significant differences in Clinical Pulmonary Infection Score, sex, age, or presence of bacteremia between the groups. A total of 496 subjects had a baseline pathogen, and 50% of subjects in each group had ≥ 2 pathogens. With the exception of Staphylococcus aureus, which was common in early-onset VAP, the pathogens (including potentially multidrug-resistant (MDR) pathogens) isolated from early-onset versus late-onset VAP were not significantly different between groups. Acinetobacter baumannii or Pseudomonas aeruginosa with decreased susceptibility to any study drug was observed in early-onset and late-onset VAP subjects. CONCLUSIONS: There were no significant differences in the prevalence of potential MDR pathogens associated with early-onset or late-onset VAP, even in subjects with prior antibiotics. Empiric therapy for early-onset VAP should also include agents likely to be effective for potential MDR pathogens. Further prospective studies should evaluate microbiology trends in subjects with VAP.

Risk assessment and counseling behaviors of healthcare professionals managing patients with chronic pain: a national multifaceted assessment of physicians, pharmacists, and their patients.

INTRODUCTION: Due to the significant and increasing problem of chronic pain in the United States, pain management is a frequent need in many healthcare settings. At the same time, there has been rising concern with the abuse/misuse and potential for addiction to opioid therapies. This study was conducted to better understand healthcare professionals' current knowledge, perceptions, and clinical practice patterns regarding prescribing of extended-release or long-acting opioid therapy to patients with chronic pain. METHODS: This study was conducted from March 2011 to May 2011; it utilized a nationally distributed case vignette survey of primary care physicians (PCPs), pain specialists, and pharmacists, along with nested chart reviews and surveys of patients with chronic pain. RESULTS: Many PCPs are inadequately performing opioid risk assessments and there is variability in interpreting a patient's opioid risk, resulting in misestimated risk. Physicians underutilize urine drug screens and written opioid use agreements when initiating opioid therapy in patients. Physicians and pharmacists often omit key messages during patient counseling about safe use of opioids and safe medication storage. Among pharmacists, safety counseling is generally limited to alerting patients to potential side effects. For most PCPs, difficulty managing patients with risk factors for opioid use and uncertainty about managing first line opioid efficacy failure are significant barriers to effective management of chronic pain. CONCLUSIONS: Patients having chronic pain and concomitant risk factors for opioid abuse, misuse, and diversion are prevalent, yet many physicians, especially PCPs, are uncomfortable managing opioid therapy in such patients. Education on best practices for risk assessment, patient monitoring during treatment, strategies for more effective counseling, patient chart documentation, and management strategies to enhance effective treatment of chronic pain are essential to ensure that PCPs and specialists maximize effective and safe use of opioid medications. Pharmacists could be a valuable member of this interdisciplinary team and should be involved in patient counseling and monitoring for aberrant behavior.

A prospective, multicenter, observational study of complicated skin and soft tissue infections in hospitalized patients: clinical characteristics, medical treatment, and outcomes.

BACKGROUND: Complicated skin and soft tissue infections (cSSTIs) occur frequently, but limited data do not allow any consensus on an optimal treatment strategy. We designed this prospective, multicenter, observational study to to explore the current epidemiology, treatment, and resulting clinical outcomes of cSSTIs to help develop strategies to potentially improve outcomes. METHODS: From June 2008 to December 2009 we enrolled a pre-specified number of adults treated in 56 U.S. hospitals with intravenous antibiotic(s) for any of the following cSSTIs: diabetic foot infection (DFI); surgical site infection (SSI); deep soft tissue abscess (DSTA); or, cellulitis. Investigators treated all patients per their usual practice during the study and collected data on a standardized form. RESULTS: We enrolled 1,033 patients (DFI 27%; SSI 32%; DSTA 14%; cellulitis 27%; mean age 54 years; 54% male), of which 74% had healthcare-associated risk factors. At presentation, 89% of patients received initial empiric therapy with intravenous antibiotics; ~20% of these patients had this empiric regimen changed or discontinued based on culture and sensitivity results. Vancomycin was the most frequently used initial intravenous antibiotic, ordered in 61% of cases. During their stay 44% of patients underwent a surgical procedure related to the study infection, usually incision and drainage or debridement. The mean length of stay was 7.1 days, ranging from 5.8 (DSTA) to 8.1 (SSI). CONCLUSION: Our findings from this large prospective observational study that characterized patients with cSSTIs from diverse US inpatient populations provide useful information on the current epidemiology, clinical management practices and outcomes of this common infection.

Extended-release/long-acting opioid REMS may fill the need for prescribers' appropriate use education.

The Food and Drug Administration (FDA) is requiring manufacturers of long-acting and extended-release opioids to have a class-wide Risk Evaluation and Mitigation Strategy (REMS). The comprehensive risk management plan will include training for prescribers on the appropriate and safe use of these pain medications. The letter dated April 19, 2011 from FDA to manufacturers outlining the REMS requirements describes voluntary training that should be certified education "where practicable." The current report includes data from a recent comprehensive study of healthcare professionals and patients and highlights key insights that can guide the development of the opioid REMS training.

A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation.

Community-acquired pneumonia (CAP) is a serious infection requiring hospitalisation in 20% of cases. The novel cephalosporin ceftobiprole has microbiological activity against the major bacterial pathogens causing CAP, including Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae, as well as against Staphylococcus aureus, including meticillin-resistant S. aureus (MRSA). This was a multicentre, double-blind study in which 706 patients with CAP severe enough to require hospitalisation were randomised to ceftobiprole or to an expert-recommended course of ceftriaxone ± linezolid (comparator group). Clinical and microbiological outcomes were determined 7-14 days after completion of therapy (test-of-cure visit). For the 469 clinically evaluable patients, cure rates were 86.6% vs. 87.4% for ceftobiprole and comparator, respectively [95% confidence interval (CI) of the difference, -6.9% to 5.3%]; in the intention-to-treat (ITT) analysis of 638 CAP patients, these cure rates were 76.4% vs. 79.3%, respectively (95% CI of the difference, -9.3% to 3.6%). A typical bacterial pathogen was identified in 29% of the ITT population. Microbiological eradication rates in the 144 microbiologically evaluable patients were 88.2% and 90.8% for the respective treatment groups (95% CI of the difference, -12.6% to 7.5%). Both study drugs were well tolerated, with but a minority of patients requiring premature discontinuation due to an adverse event (6% in the ceftobiprole group and 4% in the comparator group). The overall incidence of treatment-related adverse events was higher in the ceftobiprole group, primarily owing to differences in rates of self-limited nausea (7% vs. 2%) and vomiting (5% vs. 2%). In summary, ceftobiprole was non-inferior to the comparator (ceftriaxone ± linezolid) in all clinical and microbiological analyses conducted, suggesting that ceftobiprole has a potential role in treating hospitalised patients with CAP. [ClinicalTrials.gov identifier: NCT00326287].

Pharmaceutical industry perspective on risk evaluation and mitigation strategies: manufacturer take heed.

INTRODUCTION: Enactment of the Food and Drug Administration Amendments Act of 2007 (FDAAA) authorized the FDA to require manufacturers to submit Risk Evaluation and Mitigation Strategy (REMS) when it was deemed necessary to ensure that a drug's benefit outweigh its risk. REMS apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biologics license applications (BLAs). The objective of this review is to describe the impact of REMS requirements on the pharmaceutical industry. AREAS COVERED: Articles were identified in MEDLINE searches through October 11, 2011, using the MeSH terms and keywords pharmaceutical industry, risk management, United States Food and Drug Administration, REMS, ETASU, and Medication Guide in various combinations. EXPERT OPINION: The new powers ascribed to the FDA are notable, as they add enforceability to safety strategies that were not part of FDA's prior risk management tools, risk minimization action plans (RiskMAPs). Failure to comply with REMS can lead to financial penalties up to $10 million, and a drug could be deemed misbranded if the REMS is not followed. The new approach to risk management via FDAAA has elevated the rigor with which manufacturers must fulfill postmarketing safety commitments.

Risk evaluation and mitigation strategies (REMS): educating the prescriber.

The US FDA Amendments Act of 2007 was signed into law on 27 September 2007. A provision of this law granted the FDA new powers to enhance drug safety by requiring the pharmaceutical industry to develop Risk Evaluation and Mitigation Strategies (REMS). REMS are deemed necessary when a question exists as to whether the benefits of a drug outweigh its risks. REMS constitute a safety plan with several potential components, including a medication guide, a communication plan, elements to ensure safe use and an implementation system to help guide the prescribers, pharmacists and patients. This applies to existing drugs on the market, new drug applications (NDAs), abbreviated NDAs (generics) and biologics licence applications. REMS represent an 'upgrade' from previously required risk minimization action plans, based on the strengthening of FDA powers of authority and enforceability to incur monetary penalties against individuals representing the pharmaceutical industry who fail to comply. For illustrative purposes, we chose the drug romiplostim (Nplate®) to present an REMS, as all components were utilized to help assuage risks associated with the drug. Romiplostim is an FDA-approved drug used to treat thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura that has a significant adverse safety profile based on the risk of changes in bone marrow reticulin formation and bone marrow fibroses, and other associated risks. This review of current REMS policy is intended to provide the prescriber with a better understanding of current modalities in FDA-mandated drug safety programmes, which will impact day-to-day healthcare provider practices.

Safety and efficacy of levofloxacin 750 mg for 2 weeks or 3 weeks compared with levofloxacin 500 mg for 4 weeks in treating chronic bacterial prostatitis.

OBJECTIVE: To compare the safety and efficacy of levofloxacin 750 mg QD for 2 weeks or levofloxacin 750 mg QD for 3 weeks to levofloxacin 500 mg QD for 4 weeks in treating chronic bacterial prostatitis (CBP). RESEARCH DESIGN AND METHODS: This was a randomized, multicenter, double-blind, noninferiority study. The primary efficacy end point was investigator assessment of clinical success in the modified intent-to-treat (mITT) population at post-therapy. National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) scores were utilized to evaluate subject-reported responses post-therapy. RESULTS: A total of 241 subjects were enrolled. At post-therapy (test of cure [TOC]), clinical success rates for levofloxacin-treated subjects (750 mg QD for 3 weeks [64.9%, 48/74]) were noninferior to 500 mg QD for 4 weeks (69.3%, 52/75: 95% CI, -19.5%, 10.6%). Success rates with levofloxacin 750 mg QD for 2 weeks (63.0%, 46/73) were not noninferior to therapy with levofloxacin 500 mg QD for 4 weeks (95% CI, -21.5%, 8.9%) at TOC. At 3 and 6 months post-therapy, clinical success rates were clinically higher for the 500-mg, 4-week treatment group, and statistical analysis demonstrated both groups were not noninferior to standard therapy with levofloxacin 500 mg (95% CI, -32.5%, -0.6% for both 750-mg groups at 6 months). NIH-CPSI scores showed similar trends. Overall, adverse event (AE) rates were similar for the three treatment groups; however, discontinuation of therapy due to AEs was higher with the 750-mg dose (p = 0.02, and p = 0.13 for 750 mg, 2 weeks and 750 mg, 3 weeks versus 500 mg for 4 weeks, respectively). The main limitation of this study was that no bacterial cultures were required. CONCLUSIONS: Higher doses for shorter durations were determined to be no worse than standard therapy with levofloxacin 500 mg for a longer duration at the TOC visit. However, at the 6-month follow-up visit, the levofloxacin 750-mg dose administered for either 2 weeks or 3 weeks was inferior to the standard therapy, suggesting that a longer duration of treatment may help extend the relapse-free interval in patients with CBP. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, nct00402688.

Impact of different carbapenems and regimens of administration on resistance emergence for three isogenic Pseudomonas aeruginosa strains with differing mechanisms of resistance.

We compared drugs (imipenem and doripenem), doses (500 mg and 1 g), and infusion times (0.5 and 1.0 [imipenem], 1.0 and 4.0 h [doripenem]) in our hollow-fiber model, examining cell kill and resistance suppression for three isogenic strains of Pseudomonas aeruginosa PAO1. The experiments ran for 10 days. Serial samples were taken for total organism and resistant subpopulation counts. Drug concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry (LC/MS/MS). Free time above the MIC (time > MIC) was calculated using ADAPT II. Time to resistance emergence was examined with Cox modeling. Cell kill and resistance emergence differences were explained, in the main, by differences in potency (MIC) between doripenem and imipenem. Prolonged infusion increased free drug time > MIC and improved cell kill. For resistance suppression, the 1-g, 4-h infusion was able to completely suppress resistance for the full period of observation for the wild-type isolate. For the mutants, control was ultimately lost, but in all cases, this was the best regimen. Doripenem gave longer free time > MIC than imipenem and, therefore, better cell kill and resistance suppression. For the wild-type organism, the 1-g, 4-h infusion regimen is preferred. For organisms with resistance mutations, larger doses or addition of a second drug should be studied.

Meta-analysis of doripenem vs comparators in patients with pseudomonas infections enrolled in four phase III efficacy and safety clinical trials.

OBJECTIVE: Pseudomonas aeruginosa is a difficult-to-treat bacterial pathogen often isolated from patients with serious nosocomial infections. The goal of this analysis is to present the clinical and microbiologic effectiveness of doripenem in the treatment of infections due to P. aeruginosa. RESEARCH DESIGN AND METHODS: A meta-analysis was conducted on the subset of subjects enrolled in four randomized phase III clinical trials of doripenem in subjects with complicated intra-abdominal infections (cIAI) and nosocomial pneumonia/ventilator-associated pneumonia (NP/VAP) due to P. aeruginosa. Clinical and microbiologic success was determined by infection and across the two infections. RESULTS: Clinical success rates for modified intent-to-treat (mITT) subjects with P. aeruginosa in the cIAI and NP/VAP groups were 78.7% (37/47) and 59.6% (31/52), respectively, following treatment with doripenem versus 74.3% (26/35) and 32.8% (19/58), respectively, for subjects in the comparator groups (p < 0.05 for difference in success rates across infection types). Microbiologic eradication rates also favored doripenem, although the differences did not achieve statistical significance. The weighted difference (doripenem minus comparator) for the mITT population in clinical success rates between doripenem and the comparator agents was 16.0% (95% CI: 3.1%, 29.0%) and for microbiologic eradication rates was 9.1% (95% CI: -4.2%, 22.3%). The proportion of subjects reporting one or more treatment-emergent adverse events or serious adverse events was similar for doripenem and the comparator agents. Fourteen doripenem and 14 comparator subjects died during the study. Limitations of this retrospective meta-analysis also include the qualitative heterogeneity of the data, and a selected, narrow population of moderately ill clinical trial subjects included in the analysis. Due to limitations, these data may not be generalizable to all populations and should be considered hypothesis generating. CONCLUSION: The weighted difference in clinical success rates for subjects with cIAI and NP/VAP infections caused by P. aeruginosa was in favor of doripenem, with the relative benefit of doripenem compared with the comparator agents similar across the two infections.

Identifying exposure targets for treatment of staphylococcal pneumonia with ceftobiprole.

Ceftobiprole is a cephalosporin with potent activity against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). In order to treat patients with severe staphylococcal pneumonia, it is important to understand the drug exposure required to mediate the killing of multiple log(10) cells in a preclinical-infection model. We measured drug exposure in terms of the percentage of penetration of the drug into epithelial lining fluid (ELF) and in terms of the time for which the drug concentration was above the MIC (time>MIC) in plasma and ELF. In a murine model of staphylococcal pneumonia, we demonstrated that ceftobiprole penetrated into ELF from the plasma at a median level of nearly 69% (25th to 75th percentile range, 25 to 187%), as indexed to the ratio of values for the area under the concentration-time curve in ELF and plasma. The total-drug times>MIC in ELF that were required to kill 1 log(10) and 2 log(10) CFU/g of lung tissue were 15% and 25% of the dosing interval. We also examined the penetration of ELF by ceftobiprole in volunteers, demonstrating mean and median penetration percentages of 25.5% and 15.3%, respectively (25th to 75th percentile range, 8 to 30%). Attainment rates were calculated for kill targets of 1 log(10) and 2 log(10) CFU/g, taken from the murine model, but using the volunteer ceftobiprole ELF penetration data. The standard dose for ceftobiprole is 0.5 g every 8 h as a 2-h infusion. The attainment rates remained above 90% for 1-log(10) and 2-log(10) CFU/g kill targets at MICs of 1 and 0.5 mg/liter, respectively. Taking the expectation over the distribution of ceftobiprole MICs for 4,958 MRSA isolates showed an overall target attainment of 85.6% for a 1-log(10) CFU/g kill and 79.7% for a 2-log(10) CFU/g kill. It is important to derive exposure targets in preclinical-infection models of the infection site so that these targets can be explored in clinical trials in order to optimize the probability of a good clinical outcome.

Phase I study of aerosolized SLIT cisplatin in the treatment of patients with carcinoma of the lung.

PURPOSE: To investigate the safety and pharmacokinetics of aerosolized Sustained Release Lipid Inhalation Targeting (SLIT) Cisplatin in patients with lung carcinoma. EXPERIMENTAL DESIGN: Phase I, dose-escalating study of SLIT Cisplatin given in two sessions daily. Safety data, including laboratory variables, adverse events, pulmonary function tests, and radiographic imaging, were collected and analyzed for all patients to determine toxicity. Pharmacokinetic monitoring was done during the first course. RESULTS: Seventeen patients and one tracheostomy patient on compassionate use received treatment. Aerosolized cisplatin was well tolerated. No dose-limiting toxicity was observed at the maximum delivered dose. Safety data showed no hematologic toxicity, nephrotoxicity, ototoxicity, or neurotoxicity. Most common adverse events were nausea (64.7%), vomiting (47.1%), dyspnea (64.7%), fatigue (64.7%), and hoarseness (47.1%). Pharmacokinetic data showed very low plasma platinum levels only with the longest repeated inhalations. Common Toxicity Criteria grade 2 decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide after one course occurred both in two patients and grade one decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide in six and five patients, respectively. Direct airway deposition via the tracheostomy resulted in clinical deterioration after two cycles best described as bronchitis, completely reversible within days. Overall response: stable disease in 12 patients and progressive disease in 4 patients (one patient received one cycle). CONCLUSIONS: Aerosolized liposomal cisplatin was found to be feasible and safe.