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Objectives This analysis evaluated the clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa isolates pooled from the adult Phase III clinical trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI) or nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP). Methods Baseline isolates from five Phase III randomized controlled trials of ceftazidime/avibactam versus predominantly carbapenem comparators in patients with cIAI (RECLAIM 1 and 2; NCT01499290 and RECLAIM 3; NCT01726023), cUTI (RECAPTURE 1 and 2; NCT01595438 and NCT01599806), NP including VAP (REPROVE; NCT01808092) and cIAI or cUTI caused by ceftazidime-non-susceptible Gram-negative pathogens (REPRISE; NCT01644643) were tested for MDR status and susceptibility to ceftazidime/avibactam and carbapenem-based comparators using CLSI broth microdilution methodology. Microbiological and clinical responses for patients with ≥1 MDR Enterobacteriaceae or P. aeruginosa isolate were assessed at the test-of-cure (TOC) visit. Results In the pooled microbiologically modified ITT population, 1051 patients with MDR Enterobacteriaceae and 95 patients with MDR P. aeruginosa isolates were identified. Favourable microbiological response rates at TOC for all MDR Enterobacteriaceae and MDR P. aeruginosa were 78.4% and 57.1%, respectively, for ceftazidime/avibactam and 71.6% and 53.8%, respectively, for comparators. The proportions of patients with ≥1 MDR isolate who were clinically cured at TOC were similar in the ceftazidime/avibactam (85.4%) and comparator (87.9%) arms. Conclusions Ceftazidime/avibactam demonstrated similar clinical efficacy to predominantly carbapenem comparators against MDR Enterobacteriaceae and P. aeruginosa, and may be a suitable alternative to carbapenem-based therapies for cIAI, cUTI and NP/VAP caused by MDR Gram-negative pathogens.

Monotherapy with lefamulin, a novel, pleuromutilin antibiotic with intravenous and oral formulation options, was noninferior to moxifloxacin for efficacy and generally safe and well tolerated for community-acquired bacterial pneumonia (CABP). Lefamulin’s spectrum of activity targets bacteria that cause CABP., Background Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP. Methods In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ≥III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5–10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%). Results There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference −2.9%, 95% confidence interval [CI] g −8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference −2.6%, 95% CI −8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference −2.5%, 95% CI −8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin. Conclusions Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated. Clinical Trials Registration NCT02559310.

There is an urgent need for new strategies to reduce carbapenem consumption. Ceftazidime-avibactam was highly effective for empiric treatment of complicated urinary tract infection, including in patients with ceftazidime-nonsusceptible pathogens, and may offer an alternative to carbapenems in this setting., Background. The global emergence of carbapenem-resistant Enterobacteriaceae highlights the urgent need to reduce carbapenem dependence. The phase 3 RECAPTURE program compared the efficacy and safety of ceftazidime-avibactam and doripenem in patients with complicated urinary tract infection (cUTI), including acute pyelonephritis. Methods. Hospitalized adults with suspected or microbiologically confirmed cUTI/acute pyelonephritis were randomized 1:1 to ceftazidime-avibactam 2000 mg/500 mg every 8 hours or doripenem 500 mg every 8 hours (doses adjusted for renal function), with possible oral antibiotic switch after ≥5 days (total treatment duration up to 10 days or 14 days for patients with bacteremia). Results. Of 1033 randomized patients, 393 and 417 treated with ceftazidime-avibactam and doripenem, respectively, were eligible for the primary efficacy analyses; 19.6% had ceftazidime-nonsusceptible baseline pathogens. Noninferiority of ceftazidime-avibactam vs doripenem was demonstrated for the US Food and Drug Administration co-primary endpoints of (1) patient-reported symptomatic resolution at day 5: 276 of 393 (70.2%) vs 276 of 417 (66.2%) patients (difference, 4.0% [95% confidence interval {CI}, −2.39% to 10.42%]); and (2) combined symptomatic resolution/microbiological eradication at test of cure (TOC): 280 of 393 (71.2%) vs 269 of 417 (64.5%) patients (difference, 6.7% [95% CI, .30% to 13.12%]). Microbiological eradication at TOC (European Medicines Agency primary endpoint) occurred in 304 of 393 (77.4%) ceftazidime-avibactam vs 296 of 417 (71.0%) doripenem patients (difference, 6.4% [95% CI, .33% to 12.36%]), demonstrating superiority at the 5% significance level. Both treatments showed similar efficacy against ceftazidime-nonsusceptible pathogens. Ceftazidime-avibactam had a safety profile consistent with that of ceftazidime alone. Conclusions. Ceftazidime-avibactam was highly effective for the empiric treatment of cUTI (including acute pyelonephritis), and may offer an alternative to carbapenems in this setting. Clinical Trials Registration. NCT01595438; NCT01599806.

Summary Background Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of ceftazidime-avibactam compared with best available therapy in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens. Methods REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18–90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa . Patients were randomised (1:1) to 5–21 days of treatment with either ceftazidime-avibactam (a combination of 2000 mg ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7–10 days after last infusion of study therapy, analysed in all patients who had at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643. Findings Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 [91%; 95% CI 85·6–94·7] of 154 patients) and best available therapy (135 [91%; 85·9–95·0] of 148 patients). 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for ceftazidime-avibactam. Interpretation These results provide evidence of the efficacy of ceftazidime-avibactam as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and P aeruginosa . Funding AstraZeneca.

In this randomized phase 3 trial, ceftazidime-avibactam plus metronidazole was noninferior to meropenem in treating complicated intra-abdominal infection, with similar efficacy against ceftazidime-resistant and ceftazidime-susceptible pathogens and no new safety concerns observed., Background. When combined with ceftazidime, the novel non–β-lactam β-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239). Methods. The primary end point was clinical cure at test-of-cure visit 28–35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of −12.5%. Results. Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, −3.5%; 95% confidence interval −8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (−2.4%; −6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (−0.8%; −4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups. Conclusions. Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone. Clinical Trials Registration. NCT01499290 and NCT01500239.

Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP.In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ≥III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5-10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%).There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference -2.9%, 95% confidence interval [CI] g -8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference -2.6%, 95% CI -8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference -2.5%, 95% CI -8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin.Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated.NCT02559310.

Importance New antibacterials are needed to treat community-acquired bacterial pneumonia (CABP) because of growing antibacterial resistance and safety concerns with standard care. Objective To evaluate the efficacy and adverse events of a 5-day oral lefamulin regimen in patients with CABP. Design, Setting, and Participants A phase 3, noninferiority randomized clinical trial conducted at 99 sites in 19 countries that included adults aged 18 years or older with a Pneumonia Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; 3 or more CABP symptoms; and 2 or more vital sign abnormalities. The first patient visit was on August 30, 2016, and patients were followed up for 30 days; the final follow-up visit was on January 2, 2018. Interventions Patients were randomized 1:1 to receive oral lefamulin (600 mg every 12 hours for 5 days; n = 370) or moxifloxacin (400 mg every 24 hours for 7 days; n = 368). Main Outcomes and Measures The US Food and Drug Administration (FDA) primary end point was early clinical response at 96 hours (within a 24-hour window) after the first dose of either study drug in the intent-to-treat (ITT) population (all randomized patients). Responders were defined as alive, showing improvement in 2 or more of the 4 CABP symptoms, having no worsening of any CABP symptoms, and not receiving any nonstudy antibacterial drug for current CABP episode. The European Medicines Agency coprimary end points (FDA secondary end points) were investigator assessment of clinical response at test of cure (5-10 days after last dose) in the modified ITT population and in the clinically evaluable population. The noninferiority margin was 10% for early clinical response and investigator assessment of clinical response. Results Among 738 randomized patients (mean age, 57.5 years; 351 women [47.6%]; 360 had a PORT risk class of III or IV [48.8%]), 707 (95.8%) completed the trial. Early clinical response rates were 90.8% with lefamulin and 90.8% with moxifloxacin (difference, 0.1% [1-sided 97.5% CI, –4.4% to ∞]). Rates of investigator assessment of clinical response success were 87.5% with lefamulin and 89.1% with moxifloxacin in the modified ITT population (difference, –1.6% [1-sided 97.5% CI, –6.3% to ∞]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, –3.9% [1-sided 97.5% CI, –8.2% to ∞]) at test of cure. The most frequently reported treatment-emergent adverse events were gastrointestinal (diarrhea: 45/368 [12.2%] in lefamulin group and 4/368 [1.1%] in moxifloxacin group; nausea: 19/368 [5.2%] in lefamulin group and 7/368 [1.9%] in moxifloxacin group). Conclusions and Relevance Among patients with CABP, 5-day oral lefamulin was noninferior to 7-day oral moxifloxacin with respect to early clinical response at 96 hours after first dose. Trial Registrations ClinicalTrials.gov Identifier:NCT02813694; European Clinical Trials Identifier:2015-004782-92

Background New CABP treatments with targeted activity and improved tolerability are needed. LEF, a novel pleuromutilin antibiotic that binds to a conserved region of the bacterial ribosome, is in development for IV or oral CABP treatment. This Phase 3 clinical study evaluated the efficacy of LEF vs. MOX in adults with CABP. Methods In this multicenter, randomized, double-blind study, 551 adult patients with CABP (Patient Outcomes Research Team Risk Class ≥III) were randomized to LEF 150 mg IV Q12 hours (n = 276) or MOX 400 mg IV Q24 hours (n = 275). After 6 IV doses, qualifying patients could be switched to oral therapy. Adjunctive linezolid was given with MOX for suspected methicillin-resistant S. aureus. Primary outcomes were early clinical response (ECR) in the intent-to-treat (ITT) population (FDA endpoint), and investigator assessment of clinical response (IACR) at test of cure in the modified ITT (mITT) and clinically evaluable (CE-TOC) populations (co-primary EMA endpoints). The microITT population included all patients with a baseline CABP pathogen detected by respiratory tract or blood culture, urinary antigen test, serology, and real-time PCR from sputum, oropharyngeal and nasopharyngeal swabs. The microITT2 population included patients with a CABP pathogen detected by methods excluding PCR. Confirmatory identification and susceptibility testing of isolates, serology, and PCR were performed by a central laboratory. Results LEF was noninferior to MOX for ECR and IACR (LEF 87.3% [ITT], 81.7% [mITT], 86.9% [CE-TOC]; MOX 90.2% [ITT], 84.2% [mITT], 89.4% [CE-TOC]). The most common pathogen identified was S. pneumoniae. In the microITT population (n = 159 per arm), LEF and MOX demonstrated similar ECR and IACR rates (figure). LEF was efficacious against S. pneumoniae (including resistant phenotypes), H. influenzae, M. catarrhalis, S. aureus, and atypical pathogens. In the microITT2 population, response rates remained similar across baseline pathogens but showed more variation likely due to smaller sample sizes. Conclusion In this first Phase 3 clinical trial, LEF showed similar efficacy to MOX against the most commonly identified CABP pathogens. LEF demonstrates promise as a targeted monotherapy for the treatment of CABP in adults. Disclosures T. File, BioMerieux: Scientific Advisor, Consulting fee. Curetis: Scientific Advisor, Consulting fee. Melinta: Scientific Advisor, Consulting fee. Merck: Scientific Advisor, Consulting fee. MotifBio: Scientific Advisor, Consulting fee. Nabriva: Investigator and Scientific Advisor, Consulting fee and Research grant. Pfizer: Scientific Advisor, Consulting fee. Paratek: Scientific Advisor, Consulting fee. L. Goldberg, Nabriva: Employee, Employee Stock Options and Salary. S. Paukner, Nabriva: Employee and Shareholder, Salary. A. Das, Achaogen: Consultant, Consulting fee. Cempra: Consultant, Consulting fee. Contrafect: Consultant, Consulting fee. Paratek: Consultant, Consulting fee. Tetraphase: Consultant, Consulting fee. Wockhardt: Consultant, Consulting fee. Theravance: Consultant, Consulting fee. Zavante: Consultant, Consulting fee. UTILITY: Consultant, Consulting fee. S. P. Gelone, Nabriva Therapeutics: Employee, Equity, Shareholder and Salary. Achaogen: Shareholder, Equity, Shareholder. J. Saviski, Nabrica Therapeutics, plc: Employee, Salary. C. Sweeney, Nabriva: Employee, employee stock options and Salary. E. Seltzer, Nabriva (previous employee and salary): Employee and Shareholder, Salary. G. H. Talbot, Nabriva Therapeutics: Board Member, Consultant and Shareholder, Consulting fee and stock options, board fees. L. B. Gasink, Nabriva: Employee, Salary.

Background Lefamulin, a first in class pleuromutilin, is being developed as an IV and oral formulation for treating CABP. The second of 2 phase 3 Lefamulin Evaluation Against Pneumonia studies, LEAP 2 (NCT02813694; EudraCT 2015-004782-92) evaluating an oral 5-day regimen, is presented here. LEAP 2 complements the positive results from LEAP 1, an IV-to-oral switch study in patients with PORT Risk Class III-V. Methods In this multicenter, randomized, double-blind, double dummy study, patients with CABP were randomized to oral lefamulin 600 mg q12h for 5 days or moxifloxacin 400 mg q24h for 7 days. Adults with PORT Risk Class II–IV were eligible (≥50% were to have PORT Risk Class III or IV). The US FDA primary endpoint was early clinical response (ECR) (96 ± 24 h after first dose) in the intent-to-treat (ITT) population. The EMA coprimary endpoints (FDA secondary endpoints) were investigator assessment of clinical response (IACR) at test of cure (TOC) (5–10 days after last dose) in the modified ITT (mITT) and clinically evaluable (CE) TOC populations. For FDA and EMA endpoints, noninferiority was concluded if the lower limit of the two-sided 95% CI was greater than –10% (Figure 1). Results A total of 738 patients were randomized (n = 370 lefamulin, n = 368 moxifloxacin). Five days of lefamulin was noninferior to 7 days of moxifloxacin for both FDA and EMA primary endpoints (Figure 2). Lefamulin was efficacious regardless of PORT Risk Class (ECR responder rates for PORT II, III, and IV: 91.8% [168/183], 91.0% [132/145], and 85.0% [34/40] for lefamulin; 93.1% [176/189], 90.2% [120/133], and 85.7% [36/42] for moxifloxacin, respectively). Both agents demonstrated similar ECR responder and IACR success rates across baseline CABP pathogens. Rates of serious adverse events (AEs) and AEs leading to discontinuation were low and similar between groups. Most frequently reported AEs were gastrointestinal, the majority of mild severity with few discontinuations. Conclusion Five-day oral lefamulin demonstrated noninferiority for both FDA and EMA efficacy endpoints vs. 7-day oral moxifloxacin. Both agents were safe and generally well tolerated. Lefamulin shows promise as an oral monotherapy with a complete spectrum of antibacterial activity against CABP pathogens. Disclosures E. Alexander, Nabriva: Employee and Shareholder, Salary and Stock Options. L. Goldberg, Nabriva: Employee, Employee Stock Options and Salary. A. Das, Achaogen: Consultant, Consulting fee. Cempra: Consultant, Consulting fee. Contrafect: Consultant, Consulting fee. Paratek: Consultant, Consulting fee. Tetraphase: Consultant, Consulting fee. Wockhardt: Consultant, Consulting fee. Theravance: Consultant, Consulting fee. Zavante: Consultant, Consulting fee. Utility: Consultant, Consulting fee. Former Employee of Nabriva: Employee, Salary. Nabriva: Consultant, Consulting fee. G. J. Moran, Nabriva: Scientific Advisor, Consulting fee. C. Sandrock, Nabriva: Consultant, Consulting fee. L. B. Gasink, Former Employee of Nabriva: Employee, Salary. P. Spera, Nabriva: Employee and Shareholder, Salary. C. Sweeney, Nabriva: Employee, Employee Stock Options and Salary. S. Paukner, Nabriva: Employee and Shareholder, Salary. W. W. Wicha, Nabriva: Employee and Shareholder, Salary. J. Schranz, Nabriva: Employee and Shareholder, Salary.

Background Cytomegalovirus (CMV) disease typically occurs during the first year after solid organ transplantation, after cessation of antiviral prophylaxis. CMV occurring after the first year is uncommon and not well described. Methods We conducted a case–control study to identify potential risk factors and a retrospective cohort study to evaluate 1-month mortality in solid organ transplant (SOT) recipients who developed CMV disease after the first year post transplant, or “very late CMV” (VLCMV), compared with those developing CMV within the first year (CMV Y1), adjusting for demographics, donor and recipient CMV serostatus, immunosuppression, rejection, and co-morbidities. Results We identified 85 SOT recipients with CMV disease at a single transplant center between January 2006 and October 2008: 23 (27%) had VLCMV and 62 (73%) had CMV Y1. Heart transplantation was independently associated with increased risk (adjusted odd ratio [OR] 4.11; 95% confidence interval [CI] 1.34–12.61; P = 0.01) for VLCMV. Patients with VLCMV had increased 1-month mortality (unadjusted OR 5.39; 95% CI 1.06–27.48; P = 0.02). Mortality was uncommonly attributable to CMV. Conclusions CMV disease continues to occur after the first year post solid organ transplantation, particularly in heart transplant recipients, and can be associated with poor outcomes. CMV should be suspected in patients with symptoms or laboratory findings consistent with CMV, even if the patients present >1 year post transplant.

Background Transplant centers are reluctant to perform heart transplantation in patients with hepatitis C virus (HCV) infection because augmented immunosuppression could potentially increase mortality. However, there have been few studies examining whether HCV infection reduces survival after heart transplantation. Methods We used data from the the U.S. Scientific Registry of Transplant Recipients to perform a multicenter cohort study evaluating the association between recipient pre-transplant HCV status and survival after heart transplantation. Adults undergoing heart transplantation between January 1, 1993 and December 31, 2007 were eligible to participate. Results Among 20,687 heart transplant recipients (443 HCV-positive and 20,244 HCV-negative) at 103 institutions followed for a mean of 5.6 years, mortality was higher among HCV-positive than HCV-negative recipients (177 [40%] vs 6,367 [31.5%]; p = 0.0001). After matching on propensity score, hospital and gender, the hazard ratio (HR) of death for HCV-positive heart transplant recipients was 1.32 (95% confidence interval [CI] 1.08 to 1.61). Mortality rates were higher among HCV-positive heart transplant recipients at 1 year (9.4% vs 8.2%), 5 years (26.3% vs 22.9%), 10 years (53.1% vs 43.4%) and 15 years (74.8% vs 62.3%) post-transplantation. HRs did not vary by gender or overall number of heart transplantations performed at the center. Conclusions Pre-transplant HCV positivity is associated with decreased survival after heart transplantation.

To determine genetic factors predisposing to neurological complications following West Nile virus infection, we analyzed a cohort of 560 neuroinvasive case patients and 950 control patients for 13 371 mostly nonsynonymous single-nucleotide polymorphisms (SNPs). The top 3 SNPs on the basis of statistical significance were also in genes of biological plausibility: rs2066786 in RFC1 (replication factor C1) (P = 1.88 × 10−5; odds ratio [OR], 0.68 [95% confidence interval {CI}, .56–.81]); rs2298771 in SCN1A (sodium channel, neuronal type I α subunit) (P = 5.87 × 10−5; OR, 1.47 [95% CI, 1.21–1.77]); and rs25651 in ANPEP (ananyl aminopeptidase) (P = 1.44 × 10−4; OR, 0.69 [95% CI, .56–.83]). Additional genotyping of these SNPs in a separate sample of 264 case patients and 296 control patients resulted in a lack of significance in the replication cohort; joint significance was as follows: rs2066786, P = .0022; rs2298771, P = .005; rs25651, P = .042. Using mostly nonsynonymous variants, we therefore did not identify genetic variants associated with neuroinvasive disease.

Background.Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae is an emerging pathogen with serious clinical and infection control implications. To our knowledge, no study has specifically examined risk factors for KPC-producing K. pneumoniae or its impact on mortality.Methods.To identify risk factors for infection or colonization with KPC-producing K. pneumoniae, a case-control study was performed. Case patients with KPC-producing K. pneumoniae were compared with control subjects with carbapenem-susceptible K. pneumoniae. A cohort study evaluated the association between KPC-producing K. pneumoniae and in-hospital mortality.Results.Fifty-six case patients and 863 control subjects were identified. In multivariable analysis, independent risk factors for KPC-producing K. pneumoniae were (1) severe illness (adjusted odds ratio [AOR], 4.31; 95% confidence interval [CI], 2.25–8.25), (2) prior fluoroquinolone use (AOR, 3.39; 95% CI, 1.50, 7.66), and (3) prior extended-spectrum cephalosporin use (AOR, 2.55; 95% CI, 1.18, 5.52). Compared with samples from other anatomic locations, K. pneumoniae isolates from blood samples were less likely to harbor KPC (AOR, 0.33; 95% CI, 0.12, 0.86). KPC-producing K. pneumoniae was independently associated with in-hospital mortality (AOR, 3.60; 95% CI, 1.87–6.91).Conclusions.KPC-producing K. pneumoniae is an emerging pathogen associated with significant mortality. Our findings highlight the urgent need to develop strategies for prevention and infection control. Limiting use of certain antimicrobials, specifically fluoroquinolones and cephalosporins, use may be effective strategies.

Optimal measures for the prevention of cytomegalovirus (CMV) in high-risk orthotopic liver transplant (OLT) patients are unknown. The charts of high-risk OLT recipients with 12 months of follow-up who were transplanted over a 44-month period were reviewed. The incidence of CMV disease in CMV-seropositive donor/CMV-seronegative recipient patients receiving valganciclovir or ganciclovir prophylaxis was compared. Sixty-six patients met the inclusion criteria and were treated with 1 of 3 prophylactic regimens: valganciclovir (900 mg daily; 27 patients), oral ganciclovir (1000 mg every 8 hours; 17 patients), or intravenous ganciclovir (6 mg/kg daily; 22 patients). Eight CMV cases occurred, all after completion of the prophylaxis. The combined incidence of CMV disease with intravenous and oral ganciclovir was lower than the incidence in valganciclovir recipients (P = 0.056; relative risk, 4.33; 95% confidence interval, 0.94–19.87). CMV disease occurred in 22.2% of valganciclovir recipients, 4.5% of intravenous ganciclovir recipients, and 5.9% of oral ganciclovir recipients. In conclusion, late-onset CMV disease occurred more frequently among high-risk liver transplant recipients treated with valganciclovir prophylaxis. The 4-fold higher incidence of CMV disease in our study supports the avoidance of valganciclovir for prophylaxis in high-risk OLT patients. Liver Transpl 15:963–967, 2009. © 2009 AASLD.

During the fall of 2005, reports of personal stockpiling of oseltamivir for use during a future outbreak of H5N1 influenza virus infection were widespread, coincident with increased media coverage of the potential for a worldwide pandemic. So much oseltamivir had been prescribed prior to the start of influenza season that the drug’s manufacturer suspended shipments to the United States at the end of October 2005.1 Subsequently, despite the fact that human cases of H5N1 influenza virus infection continue to occur, public awareness has diminished, and the demand for oseltamivir has markedly decreased. In light of emerging infectious diseases and the ongoing threat of bioterrorism, personal stockpiling of other drugs in response to public health threats is likely to occur in the future. Therefore, a clearer elucidation of the issues surrounding personal stockpiling is warranted. Although stockpiling may be useful in specific contexts and certain situations, haphazard and panicked personal stockpiling of antimicrobials could decrease the availability of drugs for persons with active infection and prevent the strategic use of a limited drug supply when it is needed. Antimicrobials dispensed in anticipation of an outbreak may also be used inappropriately to treat illnesses other than those for which the drugs were intended.1 The potential ramifications of self-medication with antimicrobial drugs include the propagation of antimicrobial resistance, unwarranted risk of adverse events, and suboptimal care for individuals who should receive more extensive clinical evaluation. To our knowledge, no studies have examined patient-level prescribing and/or usage patterns for oseltamivir; in particular, there has apparently been no examination of prescribing practices and usage patterns for the oseltamivir that was prescribed out of proportion to influenza activity during periods of heightened media coverage of avian influenza. Furthermore, as far as we know, researchers have not examined the knowledge, beliefs, concerns, and/or expectations regarding avian influenza of patients who stockpiled oseltamivir. Elucidation of these issues may help illuminate the impact of personal stockpiling and develop public health responses or strategies aimed at minimizing this practice, if necessary, during future threats of pandemic illness and/or bioterrorism. Given this context, our study aimed to do the following: (1) assess individuals’ reasons for receipt of an oseltamivir prescription between September and December 2005, (2) determine the extent to which oseltamivir prescribed during this period was later used inappropriately by patients, and (3) compare knowledge, understanding, concerns, and expectations regarding avian influenza among persons who obtained oseltamivir for probable stockpiling and persons who did not obtain this drug.

Health care-acquired infections present a tremendous challenge to the care of hospitalized patients. Unfortunately, the risk of acquiring a health care-associated infection (HAI) is rising. The vast majority of HAI are of four types: urinary tract infections, surgical site infections, bloodstream infections, and pneumonia. This chapter aims to provide current data and strategies relating to the prevention of HAIs among hospitalized patients.

Eighteen patients received tigecycline as treatment for infection due to multidrug-resistant gram-negative bacilli, including Acinetobacter baumannii and Klebsiella pneumoniae carbapenemase- and extended-spectrum beta-lactamase-producing Enterobacteriaceae. Pretherapy minimum inhibitory concentration values for tigecycline predicted clinical success. Observed evolution of resistance during therapy raises concern about routine use of tigecycline in treatment of such infections when other therapies are available.

Summary Objectives Although many studies have explored the association between antimicrobial use and antimicrobial resistance, definitions of "exposure" (i.e., prior antimicrobial use) differ across such studies. Specifically, it has been noted that some studies define "exposure" as any antimicrobial use, while others require the administration of at least 24 or 48h of an antimicrobial to constitute "exposure." The impact of different definitions of exposure on final study results is unknown. We conducted the current study to determine the impact of varying the minimum threshold of prior antimicrobial use to define exposure status in studies of antimicrobial resistance. Methods We used a dataset from a prior study of risk factors for fluoroquinolone (FQ) resistant Pseudomonas aeruginosa (FQRPA) to address the study aim. Four separate multivariable models of risk factors for FQRPA were built. Each model defined a different threshold for the duration of antimicrobial administration to determine "exposure" to that antimicrobial: (1) no threshold (i.e., a subject is considered exposed if any use of the antimicrobial was documented); (2) >24h of use of the antimicrobial is necessary to be considered exposed; (3) >48h of use is required; and (4) >72h of use is required. Except for these definitions, the four multivariable models were built in exactly the same way, each using prior FQ use as the primary risk factor of interest. Results Among 872 P. aeruginosa isolates included in the original dataset, 332 (38.2%) were FQ-resistant. Each of the four multivariable models identified prior FQ use as an independent risk factor for FQRPA. However, as increasingly strict thresholds were used, the association between FQ use and FQRPA increased. Furthermore, prior use of an agent with activity against anaerobic bacteria was associated with FQRPA in models 2, 3 and 4, but not in model 1. Conclusions The use of different thresholds to define prior "exposure" to antimicrobials altered the associations between antimicrobial use and resistance. Stricter thresholds resulted in a higher estimate of the association between antimicrobial use and resistance. Furthermore, different risk factors may be identified depending on how exposure is defined. Greater attention to this issue is necessary to optimize identification of modifiable risk factors for resistance as well as accurately compare results across studies.

Objective.To identify risk factors for infection or colonization with aztreonam-resistant Pseudomonas aeruginosa and examine the impact of this organism on mortality.Design.A case-control study was performed to identify risk factors for infection or colonization with aztreonam-resistant P. aeruginosa. A cohort study was subsequently performed to examine the impact of aztreonam resistance on outcomes.Setting.A tertiary referral center in southeastern Pennsylvania.Participants.Inpatients with a clinical culture positive for P. aeruginosa between January 1, 1999, and December 31, 2000.Results.Of 720 P. aeruginosa, isolates, 183 (25.4%) were aztreonam-resistant and 537 (74.6%) were aztreonam susceptible. In a multivariable model, prior fluoroquinolone use (adjusted odds ratio [aOR], 1.81 [95% confidence interval {CI}, 1.17-2.80]), prior use of an antianaerobic agent (aOR, 1.56 [95% CI, 1.06-2.29]), and renal insufficiency (aOR, 1.59 [95% CI, 1.10-2.29]) were associated with infection or colonization with aztreonam-resistant P. aeruginosa, while older age (aOR, 0.98 [95% CI, 0.97-0.99] per year of age) was negatively associated with infection or colonization with this organism. In-hospital mortality was higher among subjects infected or colonized with aztreonam-resistant P. aeruginosa, compared with those who were infected or colonized with aztreonam-susceptible P. aeruginos (25.7% vs 16.8%;P = .009), but in multivariable analysis, no significant association was found between infection or colonization with aztreonam-resistant P. aeruginosa and mortality.Conclusions.Curbing the use of fluoroquinolones and antimicrobials with antianaerobic activity may be an effective strategy to limit the emergence of aztreonam-resistant P. aeruginosa.

The correlation of the clinical efficacies of ceftazidime-avibactam and comparators (carbapenems) was evaluated against baseline Gram-negative isolates having characterized β-lactam resistance mechanisms from complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) phase 2 trials. Enterobacteriaceae displaying ceftriaxone and/or ceftazidime MICs of ≥2 μg/ml (69 isolates) and nonfermentative Gram-negative bacilli (NF-GNB [three isolates]) with ceftazidime MICs of ≥16 μg/ml were characterized for their narrow- and extended-spectrum β-lactamase (ESBL) content. Enterobacteriaceae (one isolate) and NF-GNB (three isolates) with imipenem/meropenem MICs of ≥2 and ≥16 μg/ml, respectively, were tested for carbapenemases. All cUTI E. coli had the lineage background investigated (ST131-like versus non-ST131-like). The primary efficacy endpoint was microbiological response (eradication) at test of cure (TOC) for cUTI and clinical response (inferred microbiological eradication) at TOC for cIAI. A total of 34.1% of baseline cUTI (36.4%) and cIAI (33.1%) pathogens met the MIC-based screening criteria (screen positive). All screen-positive cUTI pathogens were CTX-M-producing E. coli , except for one E. cloacae isolate with AmpC overexpression. The majority (66.7%) of screen-positive cIAI isolates produced CTX-M-type coupled with a diverse array of other β-lactamases. Similar favorable responses were observed with ceftazidime-avibactam (93.3%) and carbapenems (90.9%), when a non-ESBL Enterobacteriaceae isolate was recovered at the baseline visit. When an ESBL Enterobacteriaceae isolate was present, the favorable responses were 85.7% and 80.0% with ceftazidime-avibactam and carbapenems, respectively. Higher favorable responses were observed with ceftazidime-avibactam (75.0%) than with carbapenems (66.7%) when an ST131-like E. coli isolate was recovered at baseline, as when a non-ST131-like isolate was present (93.8% versus 86.7%, respectively). The efficacy of ceftazidime-avibactam was similar to that of carbapenems for treatment of cUTI and cIAI caused by ESBL organisms.

Many studies have explored the association between antibiotic use and antibiotic resistance. However, methods employed in these studies to categorise prior antibiotic use (e.g. by class, by spectrum) have not been well described. The impact of using different categorisation methods on identifying risk factors for resistance is unknown. To explore these issues, we focused on extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. (ESBL-EK) as a model. First, we conducted a systematic review of studies of risk factors for ESBL-EK to characterise past approaches to categorising antibiotic use. Second, we re-analysed data from a prior study of risk factors for ESBL-EK. Two separate multivariate models of risk factors for ESBL-EK were constructed: one with prior antibiotic use categorised by class and the other with prior antibiotic use categorised by spectrum of activity. Among the 20 articles that met the inclusion criteria for the systematic review, there was tremendous variability in how prior antibiotic use was categorised (e.g. by agent, class, spectrum and/or a combination of these). No study justified its choice of categorisation method. In the re-analysis of the existing data set, multivariate models of risk factors for ESBL-EK using 'class' and 'spectrum' categorisations differed substantially. In conclusion, there has been no consistent approach to categorising antibiotic use in studies of risk factors for ESBL-EK. Different categorisation schemes were shown to have a substantial impact on study results, particularly for the antibiotic exposures associated with resistance. Elucidating these issues is critical if effective strategies to curb resistance are to be designed.

Introduction Appropriate vaccination status in the pre-solid organ transplant period is critically important. Methods To determine if lung transplant candidates are adequately vaccinated for Streptococcus pneumoniae , a cross-sectional study was performed. Electronic records of patients referred to our institution for transplantation evaluation between July 2002 and January 2004 were reviewed. Results Only 98 of 157 patients (62.4%; 95% confidence interval [CI], 54.8 to 70.1%) evaluated for lung transplantation reported prior receipt of S pneumoniae vaccine. COPD was the only factor significantly associated with vaccination. Patients with COPD were more likely to have received vaccination compared to patients with other diagnoses (odds ratio, 4.66; 95% CI, 2.26 to 9.60). Conclusions: S pneumoniae vaccination rates among potential lung transplant candidates fall substantially short of current recommendations for universal immunization. Transplant programs should thoroughly review vaccination status and develop strategies to ensure that candidates receive all appropriate vaccines before transplantation.

Bacteria and myobacteria are important pulmonary pathogens in transplant recipients and are the focus of this article. Although considerable overlap exists, there are significant differences in the epidemiology and clinical presentation of these organisms in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. The first section of this article focuses on infections in SOT recipients (predominantly heart, liver, lung, and kidney transplant recipients), and the latter addresses these infections in HSCT recipients.

Coadministration of oral divalent or trivalent cation-containing compounds with oral fluoroquinolones may impair fluoroquinolone absorption. Among 3,134 patients who received a course of oral levofloxacin, coadministration was significantly associated with subsequent identification of a levofloxacin-resistant isolate. Strategies to curb the emergence of fluoroquinolone resistance should include avoiding the coadministration of divalent or trivalent cation-containing compounds and fluoroquinolone.

We examined the possible unintended consequences of a 72-hour automatic order to discontinue vancomycin therapy in an antimicrobial stewardship program (ASP). Of 120 patients, 11 had vancomycin therapy discontinued at 72 hours without a call to the ASP, and 7 experienced a treatment interruption of 6-36 hours. All discontinuation of therapy was considered appropriate, and the 7 treatment interruptions did not have clear clinical consequences. Only one-third of patients had ASP stickers that warned of impending discontinuation of vancomycin therapy placed appropriately in the medical record.

The effect of solid-organ transplantation on the acquisition, presentation and course of leprosy is unknown. We present a case of leprosy in a heart transplant recipient with multiple unique features possibly attributed to altered immune function.

We studied exclusion policies and child care center directors' opinions regarding antibiotic use for childhood illnesses. Among 135 respondents, 96.9% reported that they had written policies on exclusion of children for acute illnesses. Although 52.4% of respondents agreed that children are prescribed antibiotics unnecessarily, 89.1% believed that parents pressure physicians to prescribe unnecessary antibiotics.

Optimal measures for the prevention of cytomegalovirus (CMV) in high-risk orthotopic liver transplant (OLT) patients are unknown. The charts of high-risk OLT recipients with 12 months of follow-up who were transplanted over a 44-month period were reviewed. The incidence of CMV disease in CMV-seropositive donor/CMV-seronegative recipient patients receiving valganciclovir or ganciclovir prophylaxis was compared. Sixty-six patients met the inclusion criteria and were treated with 1 of 3 prophylactic regimens: valganciclovir (900 mg daily; 27 patients), oral ganciclovir (1000 mg every 8 hours; 17 patients), or intravenous ganciclovir (6 mg/kg daily; 22 patients). Eight CMV cases occurred, all after completion of the prophylaxis. The combined incidence of CMV disease with intravenous and oral ganciclovir was lower than the incidence in valganciclovir recipients (P = 0.056; relative risk, 4.33; 95% confidence interval, 0.94-19.87). CMV disease occurred in 22.2% of valganciclovir recipients, 4.5% of intravenous ganciclovir recipients, and 5.9% of oral ganciclovir recipients. In conclusion, late-onset CMV disease occurred more frequently among high-risk liver transplant recipients treated with valganciclovir prophylaxis. The 4-fold higher incidence of CMV disease in our study supports the avoidance of valganciclovir for prophylaxis in high-risk OLT patients. Liver Transpl 15:963-967, 2009. (c) 2009 AASLD.

Antimicrobial-resistantpathogens pose amajor challengeto hospitals. In a recent report from the National Health-care Safety Network, a substantial percentage of health-care-associatedinfectionswerecausedbyadrug-resistantpathogen [1 ]. Nearly 60% of Staphylococcus aureus weremethicillin-resistant (MRSA), and 33% of Enterococcusspecieswerevancomycin-resistant.Fluroquinoloneresist-ance among Pseudomonas aeruginosawas 30% and carba-penem resistance among P. aeruginosa and Acinetobacterbaumannii was 23 and 29%, respectively [1 ]. Theincidence of adult Clostridium difficile hospitalizationshas doubled from 5.5cases/10000 population in 2000 to11.2cases/10000 population in 2005 [2].Determining the most effective strategy to address thesealarming trends, specifically, the role of isolation inminimizing the spread of pathogens in the healthcaresetting has been difficult. Studies of infection controlinterventions frequently use quasi-experimental design,employ multiple interventions concurrently, lack controlgroups, and insufficiently adjust for potential confoun-ders. In some circumstances, consumer interest groupsand government mandates influence practice. For emer-ging and/or less frequently encounteredpathogens,thereis often insufficient experience upon which to makedefinitive recommendations.The Healthcare Infection Control Practices AdvisoryCommittee (HICPAC) has published updated compre-hensive guidelines for isolation and management ofmultidrug-resistant organisms (MDROs) in the health-care setting [3]. More recently, Guidelines for IsolationPrecautions: Preventing Transmission of InfectiousAgents in Healthcare Settings 2007 was released byHICPAC providing detailed guidance regarding theuse of isolation for a variety of infectious diseases [4].

We assessed the impact of free on-site influenza vaccination on childcare staff vaccination prevalence using 2 before-and-after studies. Vaccination was offered during the 2003-2004 and 2006-2007 influenza seasons. Staff vaccination prevalence was higher in each intervention season compared to the prior, nonintervention season. No baseline characteristics were associated with receipt of vaccination.

The effects of contact isolation on patient satisfaction are unknown. We performed a cross-sectional survey and found that most patients lack education and knowledge regarding isolation but feel that it improves their care. In multivariable analysis, isolated patients were not less satisfied with inpatient care than were nonisolated patients.

Background Analytic approaches to the identification of risk factors for the development of drug resistance vary and may affect study results. Using fluroquinolone-resistant Pseudomonas aeruginosa (FQRPA) and imipenem-resistant P. aeruginosa as models (IRPA), we aimed to examine the effect of different approaches to classification of prior antibiotic use (i.e., class versus spectrum) on the identification of risk factors for antibiotic resistance. Methods Case–control studies to identify risk factors for FQRPA and IRPA were performed. In each, two analytic models were utilized. In the first, prior antibiotic use was classified by class, and in the other, prior antibiotic use was classified by spectrum of activity. Risk factors identified by the two models were compared qualitatively for each resistant organism. Results 879 isolates of P. aeruginosa were included in the case–control studies. Risk factors for FQRPA and IRPA identified in multivariable analyses differed based on which method of classification of prior antibiotic use was utilized. Conclusions The identification risk factors for the development of drug-resistant organisms could depend on the method of classification of prior antibiotic use. In studies of risk factors for resistant infections, the approach to classification of prior antibiotic use should be clearly stated and justified.

Objective.Many studies have investigated the association between prior antibiotic use and antibiotic resistance. However, methods used in past studies to describe the extent of prior antibiotic use (eg, use of the 2 categories exposure versus no exposure and measurement of duration of exposure) have not been reviewed. The impact of the use of different methods for quantifying the use of antibiotics is unknown. The objectives of this study were to characterize past approaches to describing the extent of antibiotic use and to identify the impact of the use of different methods on associations between use of specific antibiotics and infection with an antibiotic-resistant-organism.Methods.We conducted a systematic review of studies that investigated risk factors for extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella species to identify variability in past approaches to describing the extent of antibiotic use. We then reanalyzed a data set from a prior study of risk factors for infection with ESBL-producing E. coli and Klebsiella species. We developed 2 separate multivariable models: 1 in which prior antibiotic use was described as a categorical variable (eg, exposure or no exposure) and 1 in which antibiotic use was described as a continuous variable (eg, measured in antibiotic-days). These models were compared qualitatively.Setting.Large academic medical center.Results.The 25 articles included in the systematic review revealed a variety of methods used to describe the extent of prior antibiotic exposure. Only 1 study justified its approach. Results from the 2 multivariable models that used different methodologic approaches differed substantially. Specifically, use of third-generation cephalosporins was a risk factor for infection with ESBL-producing E. coli and Klebsiella species when antibiotic use was described as a continuous variable but not when antibiotic use was described as a categorical variable.Conclusions.There has been no consistent method for assessing the extent of prior antibiotic exposure. The use of different methods may substantially alter the identified antimicrobial risk factors, which has important implications for the resultant interventions regarding antimicrobial use.

Ultrasensitive assays for HIV RNA have identified a significant number of patients with persistent low-level viremia despite antiretroviral therapy. The clinical implications of maintaining antiretroviral therapy during low-level HIV viremia remain unclear. The primary objective of this study was to determine the rate and risk factors for virological increase in subjects with low-level HIV viremia who did not change antiretroviral therapy. Between July 1998 and February 2002, we retrospectively observed 79 HIV-infected adults with low-level HIV viremia (between 50 and 500 copies per milliliter) who had been on a stable antiretroviral regimen for at least 3 months and continued that regimen for at least 3 more months. Virologic increase, defined as HIV RNA levels greater than 1000 copies per milliliter, was observed in 29 of the 79 (37%) subjects. The CD4 cell counts decreased by a median of 1.8 cells/mm(3) per month (interquartile range [IQR], -19.6 to 2.3 cells/mm3) in this group but increased by a median of 0.5 cells/mm3 per month (IQR, -6.3 to 5.8 cells/mm3) in the 50 subjects who did not experience virologic increase. A Kaplan-Meier estimate showed that at 3 years of follow-up, approximately 40% of the observed cohort had not experienced virologic increase. There was a higher rate of virologic increase per log increase in HIV viral load at entry into the cohort (adjusted hazards ratio [HR] 3.7; 95% confidence interval [CI], 1.1 to 12.6). Subjects of white race were also more likely to experience virological increase (adjusted HR 2.6; CI, 1.2 to 5.8). Maintenance of antiretroviral therapy despite low-level HIV viremia provided sustained immunological benefit over a 2-year period in approximately two thirds of our cohort. Higher initial HIV RNA levels and white race were predictors for virologic increase.

Although liberalization of donor criteria could expand the donor pool, the use of certain "marginal donors," such as those who are hepatitis C virus (HCV) positive, is controversial. Little is known about the effect of donor HCV positivity on survival in cardiac transplantation.To examine the association between donor HCV positivity and survival among heart transplant recipients and to determine the effects of recipient age and recipient HCV status on this association.A multicenter cohort study was performed using the US Scientific Registry of Transplant Recipients. Adult heart transplant patients who received their transplants between April 1, 1994, and July 31, 2003, were eligible for inclusion.All-cause mortality.Of 10 915 patients meeting entry criteria, 261 received an HCV-positive donor heart. Mortality was higher among recipients of HCV-positive donor hearts at 1 year (16.9% vs 8.2%; P.001), 5 years (41.8% vs 18.5%; P.001), and 10 years (50.6% vs 24.3%; P.001). Using Kaplan-Meier methods, 1-, 5-, and 10-year survival rates were 83%, 53%, and 25%, and 92%, 77%, and 53% for recipients of HCV-positive and HCV-negative donor hearts, respectively (P.001, log-rank test). Recipients of HCV-positive donor hearts were more likely to die of liver disease and coronary vasculopathy. After propensity matching, the overall hazard ratio (HR) associated with receipt of an HCV-positive donor heart was 2.10 (95% confidence interval [CI], 1.60-2.75). Stratified analyses showed that HRs did not vary by recipient HCV status or by recipient age (for recipients aged 18-39 years: HR, 1.75 [95% CI, 0.70-4.40]; for recipients aged 40-59 years: HR, 2.23 [95% CI, 1.42-3.52]; and for recipients aged 60 years and older: HR, 2.07 [95% CI, 1.32-3.27]; overall P value for interaction,.10).Receipt of a heart from an HCV-positive donor is associated with decreased survival in heart transplant recipients. This association appears to be independent of recipient HCV status and age. Preferential allocation of HCV-positive donors to HCV-positive recipients and/or older recipients is not warranted.

Purpose Pseudomonas aeruginosa infections have been associated with considerable morbidity and mortality. Fluoroquinolones (FQ) are the only oral therapy available for P. aeruginosa infections, but resistance is increasingly prevalent. Methods We examined annual trends in FQ-resistant P. aeruginosa (FQRPA) from 1991 to 2000. Subsequently, inpatients with a clinical culture positive for P. aeruginosa between January 1, 1999 and December 31, 2000 were included in a case control study to identify risk factors for FQ resistance and a cohort study to examine the impact of FQ resistance on outcomes in P. aeruginosa . Results Annual prevalence of FQRPA increased from 15% in 1991 to 41% in 2000 ( P P. aeruginosa isolates were FQ resistant and 540 were FQ susceptible. Prior FQ use was the only independent risk factor for FQRPA (adjusted OR=3.43; 95% confidence interval [CI] 2.37, 4.96). Subjects with FQRPA had greater median hospital charges ($62,325 vs $48,734) ( P =.007) and higher mortality (47.5% vs 35.5%) ( P =.004). However, in a multivariate model, only imipenem resistance of the isolate was significantly associated with mortality. FQ resistance was not an independent risk factor. Conclusions FQRPA has increased significantly and is associated with prior FQ use. Limiting FQ use may curb the emergence of resistance among P. aeruginosa. FQRPA is associated with increased hospital charges, but other resistance patterns may have a more significant impact on mortality.