Wound Culture Utility in Negative Surgical Exploration for Necrotizing Soft Tissue Infection.

Early surgical intervention decreases mortality in necrotizing soft tissue infections (NSTIs). Yet, a subset of patients will not have NSTIs (non-NSTIs) at the time of exploration. We hypothesized that NSTI and non-NSTI patients had similar causative organisms and that intraoperative wound cultures could help guide management. Culture results and outcomes were compared for all patients undergoing surgery for suspected NSTIs over a seven-year-period. Of 295 patients, 240 (81.4%) had NSTIs. Of the 55 non-NSTI patients (18.6%), 50 had cellulitis and 5 had abscesses. NSTI and non-NSTI patients had similar rates of bacteremia (20.4% vs 17.6%, P = 0.66), septic shock (15.9% vs 12.7%, P = 0.68), and mortality (10.4% vs 7.2%, P = 0.62). Wound cultures were collected more often in NSTI patients (229/240, 95.4%) than in non-NSTI patients (42/55, 76.4%, P < 0.01). Non-NSTI patients had positive deep wound cultures more than half of the time (23/42, 54.8%). The microbiologic profile was similar between groups, with Methicillin Resistant Staphylococcus aureus and Group A Streptococcus occurring with the same frequency. We advocate for deep wound cultures in all patients being evaluated operatively for NSTIs even if the exploration is considered negative because these patients have similar clinical characteristics and virulent microbiology, and culture results can help guide antimicrobial therapy.

Chance to cut: defining a negative exploration rate in patients with suspected necrotizing soft tissue infection.

BACKGROUND: Necrotizing soft tissue infections (NSTI) are aggressive infections associated with significant morbidity and mortality. Despite multiple predictive models for the identification of NSTI, a subset of patients will not have an NSTI at the time of surgical exploration. We hypothesized there is a subset of patients without NSTI who are clinically indistinguishable from those with NSTI. We aimed to characterize the differences between NSTI and non-NSTI patients and describe a negative exploration rate for this disease process. METHODS: We conducted a retrospective review of adult patients undergoing surgical exploration for suspected NSTI at our county-funded, academic-affiliated medical center between 2008 and 2015. Patients were identified as having NSTI or not (non-NSTI) based on surgical findings at the initial operation. Pathology reports were reviewed to confirm diagnosis. The NSTI and non-NSTI patients were compared using χ2 test, Fisher's exact test, and Wilcoxon rank-sum test as appropriate. A p value <0.05 was considered significant. RESULTS: Of 295 patients undergoing operation for suspected NSTI, 232 (79%) were diagnosed with NSTI at the initial operation and 63 (21%) were not. Of these 63 patients, 5 (7.9%) had an abscess and 58 (92%) had cellulitis resulting in a total of 237 patients (80%) with a surgical disease process. Patients with NSTI had higher white cell counts (18.5 vs. 14.9 k/mm3, p=0.02) and glucose levels (244 vs. 114 mg/dL, p<0.0001), but lower sodium values (130 vs. 134 mmol/L, p≤0.0001) and less violaceous skin changes (9.2% vs. 23.8%, p=0.004). Eight patients (14%) initially diagnosed with cellulitis had an NSTI diagnosed on return to the operating room for failure to improve. CONCLUSIONS: Clinical differences between NSTI and non-NSTI patients are subtle. We found a 20% negative exploration rate for suspected NSTI. Close postoperative attention to this cohort is warranted as a small subset may progress. LEVEL OF EVIDENCE: Retrospective cohort study, level III.

Routine repeat head CT may not be necessary for patients with mild TBI.

BACKGROUND: Routine repeat cranial CT (RHCT) is standard of care for CT-verified traumatic brain injury (TBI). Despite mixed evidence, those with mild TBI are subject to radiation and expense from serial CT scans. Thus, we investigated the necessity and utility of RHCT for patients with mild TBI. We hypothesized that repeat head CT in these patients would not alter patient care or outcomes. METHODS: We retrospectively studied patients suffering from mild TBI (Glasgow Coma Scale (GCS) score 13-15) and treated at the R Adams Cowley Shock Trauma Center from November 2014 through January 2015. The primary outcome was the need for surgical intervention. Outcomes were compared using paired Student's t-test, and stratified by injury on initial CT, GCS change, demographics, and presenting vital signs (mean ± SD). RESULTS: Eighty-five patients met inclusion criteria with an average initial GCS score=14.6±0.57. Our center sees about 2800 patients with TBI per year, or about 230 per month. This includes patients with concussions. This sample represents about 30% of patients with TBI seen during the study period. Ten patients required operation (four based on initial CT and others for worsening GCS, headaches, large unresolving injury). There was progression of injury on repeat CT scan in only two patients that required operation, and this accompanied clinical deterioration. The mean brain Abbreviated Injury Scale (AIS) score was 4.8±0.3 for surgical patients on initial CT scan compared with 3.4±0.6 (P<0.001) for non-surgical patients. Initial CT subdural hematoma size was 1.1±0.6 cm for surgical patients compared with 0.49±0.3 cm (P=0.05) for non-surgical patients. There was no significant difference between intervention groups in terms of other intracranial injuries, demographics, vital signs, or change in GCS. Overall, 75 patients that did not require surgical intervention received RHCT. At $340 per CT, $51 000 was spent on unnecessary imaging ($367 000/year, extrapolated). DISCUSSION: In an environment of increased scrutiny on healthcare expenditures, it is necessary to question dogma and eliminate unnecessary cost. Our data questions the use of routine repeat head CT scans in every patient with anatomic TBI and suggests that clinically stable patients with small injury can simply be followed clinically. LEVEL OF EVIDENCE: Level III.

Activity-based exposure comparisons among humans and nonclinical safety testing species in an extensively metabolized drug candidate.

1. Extensive metabolism of a drug candidate can complicate the interpretation of comparative safety and efficacy data from humans and preclinical species. 2. The 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor, AMG 221 underwent extensive oxidative metabolism to structurally similar but differentially active primary and secondary metabolites. Relative potency data from synthetic metabolites enabled a stepwise quantitative assessment of AMG 221 in vivo metabolism that compared relative exposure to metabolites in plasma across species and discerned which active metabolites to monitor in preclinical and clinical safety and efficacy studies. 3. Pooled plasma samples from AMG 221-dosed human subjects were profiled using high-resolution liquid chromatography-mass spectrometry (LC-MS) with a mass-defect-filter. The most abundant peak, M1 accounted for 47%-59% of peaks followed by AMG 221 at 27%-40%. Other metabolites were each less than 7%. Activity-normalized data indicated both M1 and AMG 221 should be monitored to assist pharmacokinetic-pharmacodynamic (PK-PD) modeling. 4. Rat and dog area under the plasma concentration time curve (AUC) exposures to M1 at preclinical no observable adverse effect level (NOAEL) doses were 2-42-fold higher than human, indicating M1 was not a disproportionate metabolite, as defined by International Committee on Harmonization (ICH) M3(R2) guidance. 5. Development decisions regarding active metabolite monitoring and potentially disproportionate metabolites in extensively metabolized drug candidates are enabled by metabolite synthesis and liquid chromatography high-resolution mass spectrometry (LC-HRMS)-based assessment of potency-normalized plasma metabolite AUCs.

Regiospecific and stereospecific triangulation of the structures of metabolites formed by sequential metabolism at multiple prochiral centers.

Structures of in vivo secondary metabolites of a norbornane-containing drug candidate with multiple prochiral centers were triangulated, in a regio- and stereospecific fashion, using in vitro metabolism data from synthetic primary metabolites and in vivo metabolism data from the separate administration of a radiolabeled primary metabolite, [(14)C]-(S)-2-((1R,2S,4R,5S)-5-hydroxybicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (M1). A mass balance study on the 11ß hydroxysteroid dehydrogenase type 1 enzyme inhibitor [(14)C]-(S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221) in rats was dosed at 2 mg/kg. Radioactivity was excreted mainly in urine. Metabolites of AMG 221 were quantified by high-performance liquid chromatography with radiometric detection and characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS revealed at least 38 metabolites. Seven monohydroxylated metabolites mediated formation of the other 31 metabolites. Twenty-eight metabolites were identified regio- and stereo-specifically. Little parent drug was observed in urine or feces. Monohydroxy metabolite M1 was the major metabolite comprising 17 to 24% of excreted dose, and seven monohydroxy metabolites comprised 29 (male) and 37% (female) of dose. Of 11 quantifiable isobaric dihydroxy metabolites that comprised 8.3 (male) and 24% (female) of dose, 10 were identified regio- and stereospecifically by triangulation. A single trihydroxy metabolite comprised approximately 10% of dose. Complex secondary metabolism of drugs with multiple prochiral centers can be elucidated in a regio- and stereospecific fashion without NMR through synthesis and in vitro and in vivo studies on the metabolism of chiral primary oxidation products.