Time Course and Extent of Renal Function Changes in Patients Receiving Treatment for Staphylococcal Pneumonias: An Analysis Comparing Telavancin and Vancomycin from the ATTAIN Trials.

STUDY OBJECTIVE: Telavancin and vancomycin are both approved for treatment of hospital-acquired and ventilator-associated bacterial pneumonias caused by Staphylococcus aureus, and both agents can cause renal dysfunction. The objective of this study was to assess renal function changes by performing renal shift table analyses of telavancin- and vancomycin-treated patients in phase III trials. DESIGN: Retrospective, descriptive analysis of data from the safety population from the Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia (ATTAIN) trials. PATIENTS: A total of 1503 adults with hospital-acquired or ventilator-associated bacterial pneumonia primarily caused by gram-positive pathogens and who received telavancin (n = 751) or vancomycin (n = 752). MEASUREMENTS AND MAIN RESULTS: Decline or improvement in creatinine clearance (CrCl) across seven defined categories (≤30, >30-40, >40-50, >50-60, >60-70, >70-80, and >80 ml/min) was classified as negative or positive shifts, respectively. The number of categories crossed (either positive or negative) determined the grade of shift (of a potential grades 1-6, with crossing from one category to the next adjacent category defined as a grade 1 shift) at specific time points compared with baseline: day 4, day 7, and end of therapy (EOT). Approximately 77%-91.6% of patients had either no change or improvement of CrCl across all time points for both treatments. Negative shifts were consistent for telavancin (day 4, 19.3%; day 7, 19.0%; EOT, 23.0%) but increased over time for vancomycin (day 4, 8.4%; day 7, 12.3%; EOT, 19.3%). A significantly lower proportion of patients receiving vancomycin showed renal function decline on day 4 and day 7. At EOT, negative shift rates were similar between treatments (treatment difference 3.6% [95% CI -0.7 to 7.9]). At day 7 and EOT, a higher percentage of vancomycin-treated patients experienced high-grade negative shifts relative to telavancin (day 7, vancomycin 2.8% vs telavancin 1.9%; EOT, vancomycin 4.7% vs telavancin 4.1%), though differences were not statistically significant. CONCLUSION: Use of shift tables revealed differences in timing of renal function changes in patients receiving telavancin and vancomycin. Telavancin-related declines in renal function were similar at day 4 and day 7, with a slight increase by EOT. This differed from vancomycin, which caused a steady increase in the percentage of patients with renal function decline over time. A significant difference in negative renal shifts between treatments occurred at day 4 and day 7 and favored vancomycin; however, the difference was minimal and not significant at EOT.

Telavancin hospital-acquired pneumonia trials: impact of Gram-negative infections and inadequate Gram-negative coverage on clinical efficacy and all-cause mortality.

BACKGROUND: When hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is caused by gram-positive and gram-negative pathogens or both (mixed infections), the adequacy of gram-negative coverage (GNC) can confound the assessment of a gram-positive agent under study. This analysis examines the influence of gram-negative infections and the adequacy of GNC on clinical efficacy and all-cause mortality in the telavancin HABP/VABP phase 3 ATTAIN trials (Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia). METHODS: This post hoc analysis evaluated 3 patient groups from ATTAIN: (1) gram-positive-only infections, (2) gram-positive-only and mixed infections-adequate GNC, and (3) gram-negative-only infections and mixed infections with inadequate GNC. For each, clinical efficacy at test of cure and all-cause mortality at day 28 were compared for telavancin and vancomycin. RESULTS/CONCLUSIONS: In the ATTAIN safety population there were 16 more deaths in the telavancin arms than in the vancomycin arms. Of these, 13 were in patients with gram-negative-only infections (n = 9) or with mixed infections and inadequate GNC (n = 4) and all had estimated baseline creatinine clearances of <30ml/min. Based on this analysis, clinical response and all-cause mortality could be confounded because there were more patients with gram-negative pathogens at baseline and more patients received inadequate treatment of these gram-negative infections in the telavancin groups.

Readministration of drotrecogin alfa (activated) in an adult with severe sepsis.

PURPOSE: The case of a patient with severe, multidrug-resistant, postoperative sepsis who was successfully treated with drotrecogin alfa (activated) on two occasions is reported. SUMMARY: After a thigh debridement procedure, a 55-year-old African-American woman developed systemic inflammatory response syndrome (SIRS) secondary to necrotizing fasciitis. Despite empiric treatment including piperacillin-tazobactam and vancomycin, the patient remained severely hemodynamically unstable, exhibiting signs of multiorgan failure and requiring mechanical ventilation and the placement of a tracheostomy tube. After the administration of i.v. drotrecogin alfa (activated) 160 mg (24 µg/kg/hr) over 96 hours in combination with standard i.v. antimicrobials and vasopressin, the patient's hemodynamic status improved considerably. About three weeks later, the patient again developed SIRS that was refractory to standard therapies. After the results of laboratory cultures indicated ventilator-associated pneumonia due to multidrug-resistant Klebsiella pneumoniae, the woman received a second course of drotrecogin alfa and other therapies. Her condition improved and she was extubated and eventually transferred to a medical-surgical unit for continued care. While drotrecogin alfa, a recombinant form of human activated protein C (APC), has been shown to reduce mortality in adults with severe sepsis and acute organ dysfunction, previous reports indicated an increased risk of thrombotic events with the use of the drug, and there is speculation that the development of anti-APC antibodies might result in a diminished therapeutic response. In the case described here, there were no thrombotic events during or after either drotrecogin alfa infusion and no clinical evidence of antibody formation. CONCLUSION: A patient received two complete courses of drotrecogin alfa (activated) without any treatment-related complications.

Treatment of Eikenella corrodens and Actinomyces odontolyticus foot abscess in a penicillin-allergic patient.

OBJECTIVE: To report a case of Eikenella corrodens and Actinomyces odontolyticus foot abscess secondary to a toothpick puncture in a penicillin-allergic patient that was successfully treated with a long-term course of doxycycline. CASE SUMMARY: A 39-year-old woman with diabetes mellitus type 2 and hyperlipidemia presented with difficulty ambulating as well as pain and swelling of her right foot. Prior to presentation, she sustained a toothpick puncture to her right foot; she removed the toothpick intact and did not know whether it had been used. Due to a penicillin allergy, she began treatment with levofloxacin, which was changed to clindamycin one day later. The patient was diagnosed with right Achilles tendonitis/cellulitis and was discharged on a one-week course of clindamycin. Twenty-five days later she was readmitted, complaining of pain and swelling in the same area, which this time presented as an abscess. Upon this admission, vancomycin and levofloxacin were initiated and incision and drainage (I & D) was performed. Cultures and sensitivities from I & D were significant for E. corrodens and A. odontolyticus, and treatment was changed to intravenous doxycycline 100 mg every 12 hours for 10 weeks. Oral doxycycline 100 mg every 12 hours was then used for 3 months, and treatment was successful. DISCUSSION: E. corrodens and A. odontolyticus are 2 slow-growing organisms that are part of the normal oropharyngeal flora. Extraoral infections due to either of these organisms may be difficult to treat and might need lengthier treatments than are necessary for most infections. First-line treatment for such infections is penicillins and cephalosporins; however, in a patient with penicillin allergy, treatment options become limited, as there is potential cross-reactivity with other agents. CONCLUSIONS: Patients with infections secondary to E. corrodens and/or A. odontolyticus in whom penicillin allergy is a concern can be treated effectively with doxycycline.