Background Vancomycin is the most commonly administered antibiotic in hospitalized patients, but optimal exposure targets remain controversial. To clarify the therapeutic exposure range, this study evaluated the association between vancomycin exposure and outcomes in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Methods This was a prospective, multicenter (n = 14), observational study of 265 hospitalized adults with MRSA bacteremia treated with vancomycin. The primary outcome was treatment failure (TF), defined as 30-day mortality or persistent bacteremia ≥7 days. Secondary outcomes included acute kidney injury (AKI). The study was powered to compare TF between patients who achieved or did not achieve day 2 area under the curve to minimum inhibitory concentration (AUC/MIC) thresholds previously found to be associated with lower incidences of TF. The thresholds, analyzed separately as co-primary endpoints, were AUC/MIC by broth microdilution ≥650 and AUC/MIC by Etest ≥320. Results Treatment failure and AKI occurred in 18% and 26% of patients, respectively. Achievement of the prespecified day 2 AUC/MIC thresholds was not associated with less TF. Alternative day 2 AUC/MIC thresholds associated with lower TF risks were not identified. A relationship between the day 2 AUC and AKI was observed. Patients with day 2 AUC ≤515 experienced the best global outcomes (no TF and no AKI). Conclusions Higher vancomycin exposures did not confer a lower TF risk but were associated with more AKI. The findings suggest that vancomycin dosing should be guided by the AUC and day 2 AUCs should be ≤515. As few patients had day 2 AUCs <400, further study is needed to define the lower bound of the therapeutic range.

BackgroundCurrent guidelines recommend vancomycin (VAN) dosing to achieve AUC/MIC ratio ≥400 for patients (pts) with serious MRSA bloodstream infections (BSI), but supporting data were largely derived in single center retrospective studies. A recent study using a Bayesian approach to estimate the VAN AUC found that patients with MRSA BSI who had an AUCDAY2/MICBMD ≥ 650 or an AUCDAY2/MICETEST ≥ 320 had lower incidences of failure (Clin Infect Dis 59:666, 2014). This study prospectively evaluated if these VAN AUCDAY2/MIC targets were associated with lower incidences of failure (PROVIDE, Award number UM1AI104681, Antibacterial Resistance Leadership Group).MethodsProspective, multi-center (n = 14), observational study (2014–2106) of hospitalized adults with confirmed MRSA BSI treated with VAN ≥ 72h. Exclusion: (1) neutropenia; (2) cystic fibrosis; (3) renal replacement therapy; (4) APACHE-II score > 25; (5) previous MRSA BSI within 60 days. VAN exposures were estimated using maximum a posteriori probability procedure in ADAPT 5. MICBMD and MICETEST were performed at a central laboratory. Outcomes: failure (30-day mortality or MRSA BSI ≥ 7 days); acute kidney injury (AKI), ≥1.5 × increase in serum creatinine (Scr) among patients with a baseline SCR < 2.0mg/dl. The study was powered at 80% to detect a 17.5% difference in failure between AUCDAY2/MIC groups.ResultsAmong the 265 evaluable patients, mean (SD) age was 61 (17) and APACHE-II was 12 (6). Endocarditis was definite/possible in 29%. The MIC50/90 by BMD and ETEST were 1/1 and 1.5/1.5mg/l, respectively. Failure occurred in 18%; 26% had AKI. Mean (SD) VAN duration was 18 (14) days. Mean (SD) AUCDAY2 was 586.9 (235.5) and 44% and 73% of patients achieved an AUCDAY2/MICBMD ≥ 650 and AUCDAY2/MICETEST ≥ 320. In the multivariate analyses (Figure 1), failure was not significantly different between AUCDAY2/MIC groups. In contrast, AKI was significantly more common in patients with an AUCDAY2/ MICETEST > = 320.ConclusionAchievement of higher VAN AUCDAY2/MIC exposures for patients with MRSA BSIs were not associated with better outcomes and were found to result in increased AKI. Clinicians should assess the benefits vs. risks of using VAN regimens that confer high AUCDAY2/MIC exposures for patients with MRSA BSIs.Disclosures T. P. Lodise Jr., allergan: Consultant, Grant Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium; medicines company: Consultant, Grant Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium; melinta: Consultant, Consulting fee; motif: Consultant and Scientific Advisor, Consulting fee; paratek: Consultant and Scientific Advisor, Consulting fee; nabriva: Consultant, Consulting fee; M. J. Zervos, Merck, Inc.: Investigator, Research grant; M. Scheetz, Bayer: Scientific Advisor, Consulting fee; V. Fowler Jr., Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, ...

Pasteurella multocida is a gram-negative coccobacillus that causes a spectrum of illnesses. P multocida lives as commensal bacteria in the upper respiratory tracts of fowl and mammals. Infections most commonly result from cat or dog bites; however, direct inoculation via saliva has been reported. Although the majority of P. multocida infections manifest in skin and soft tissue, it may cause bacteremia with disseminated infection in an immunocompromised host. Dissemination is responsive to treatment but carries a significant mortality risk of about 30%. We present a case of a 46 year old male with type 2 diabetes mellitus, coronary artery disease and chronic kidney disease with stage 4 neuropathic heel ulcer who presented with hypothermia and chills. One day into admission, 4/4 blood culture bottles were positive for Pasteurella multocida. MRI of the foot was concerning for osteomyelitis which was confirmed via I&D. The patient did report having a dog and a cat at home, but adamantly denied any bites from either animal. Examination of his boot used for support with his foot containing the ulcer revealed extensive animal hair stuck to the boot. It was deemed likely that the route of inoculation occurred from contamination of his neuropathic ulcer from his dog's saliva, likely from a lick, for which his diabetic neuropathy may have impaired initial sensation of the contamination. The patient was treated with ampicillin-sulbactam while admitted and discharged with oral levofloxacin 6 week course for residual osteomyelitis.

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