Baseline Characteristics and Outcomes for People With and Without COVID-19 Diagnoses Receiving Inpatient Rehabilitation Care Across the US in 2020-2021.

Objective: To assess sociodemographic, medical complexity, and outcomes of persons receiving care at inpatient rehabilitation facilities (IRFs) with and without a diagnosis of COVID-19. Design: A retrospective cohort study using electronic medical record (EMR) data from 138 IRFs across 34 states and Puerto Rico. Setting: N/A. Participants: IRF EMR data for 212,663 patients discharged between 04/01/2020 and 05/31/2021 (N=212,663), of which 16,199 (COVID-19 group) had a primary or secondary COVID-19 diagnosis based upon ICD codes set (ICD-10 codes U07.1, B94.8, Z86.19, Z86.16). Main Outcome Measures: Four categories: (a) sociodemographic, (b) medical complexity, (c) process, that is, standard IRF processes, and clinical outcomes (collected routinely as part of administrative reporting), and (d) functional outcomes. Patients with missing functional data associated with short/incomplete stays (n=623) were excluded from analysis of functional outcomes category only. Standard descriptive analysis techniques were employed for comparing categorical and continuous variables between groups. Results: Statistically significant differences were noted between the COVID-19 group and non-COVID groups for race (26.0% vs 19.7% non-minority, P<.001), Case Mix Index (1.49 vs 1.46, P<.001), Center for Medicare and Medicaid Services 60% rule qualification (79.0% vs 73.4%, P<.001), time to onset (24.3 vs 18.0 days, P<.001), length of stay (14.2 vs 12.9 days, P<.001), and discharge disposition (to community: 75.3% vs 81%, P<.001; to acute care facility: 15.6% vs 10.8%, P<.001). The COVID-19 group had higher frequency of respiratory and cardiovascular disease, diabetes, encephalopathy, morbid obesity, and critical illness neuropathy and myopathy. Clinically insignificant differences were noted for age, sex, depression, and cognitive assessment. Ability to participate and functional outcomes were comparable between the groups. Conclusion: There are significant differences between the COVID-19 and non-COVID group in some sociodemographic, medical complexity, process and clinical outcomes, but not in functional outcomes. The ability to participate in the IRF-required intensity of therapy services along with attainment of comparable levels of functional outcomes supports the benefit of IRFs for persons with COVID-19.

Innovations in Evaluating Statin Benefit and Efficacy in Staphylococcus aureus Intracellular Infection Management.

An emerging therapeutic approach in the treatment of infectious disease is to augment the host response through repurposing of well-tolerated, non-antibiotic, host-directed therapeutics. Earlier retrospective studies identify a positive association between statin use and a decreased risk of death due to sepsis or bacteremia. However, more recent randomized control trials fail to detect a therapeutic benefit in these complex infection settings. It is postulated that unrecognized biases in certain observational studies may have led to an overestimation of benefit and that statin use is instead a marker for health status, wealth, and demographic characteristics which may separately affect death due to infection. What remains unresolved is that in vitro and in vivo evidence reproducibly indicates that statin pharmacology limits infection and augments immunomodulatory responses, suggesting that therapeutic benefits may be attainable in certain infection settings, such as intracellular infection by S. aureus. Carefully considering the biological mechanisms capable of driving the relationship between statins and infections and constructing a methodology to avoid potential biases in observational studies would enable the examination of protective effects against infection and limit the risk of underestimating statin efficacy. Such an approach would rely on the examination of statin use in defined infection settings based on an underlying mode-of-action and pharmacology, where the inhibition of HMG-CoA-reductase at the rate-limiting step in cholesterol biosynthesis diminishes not only cholesterol levels but also isoprenoid intermediates central to host cell invasion by S. aureus. Therapeutic benefit in such settings, if existent, may be of clinical importance.

Cytologic analysis of a glomus tumor in the left second toe: Case report.

We present a 66-year-old female with a glomus tumor diagnosed by fine-needle aspiration (FNA) at the subungual region of her left second toe. Cytologic findings include cohesive clusters of round, uniform cells with scant cytoplasm. Nuclei were monotonous with fine chromatin. No cellular atypia, nuclear inclusions, mitotic figures, nor nucleoli were identified. Cells were surrounded by thick wisps of magenta colored myxoid material reminiscent of a pleomorphic adenoma. Few spindle shaped cells could be seen near the border of the tumor clusters. Staining was positive for alpha-smooth muscle actin. This case report presents one of few FNA diagnosed glomus tumors.

A Mixed Methods Approach to Improving Provider Counseling of Patients Who Vape.

Significance: Vaping is an epidemic among young people, but there is little guidance on how medical providers should counsel young adults about vaping. To address this gap, we examined how electronic health record (EHR) systems prompt providers to collect vaping data and interviewed young adults about vaping communications with providers and preferred information sources. Methods: In this mixed methods study, we used survey research methods to explore if prompts exist in EHR systems to guide discussions about vaping with youth seen in primary care. We collected primary care practice information about EHR prompts regarding e-cigarette use from 10 rural North Carolina practices from August 2020 through November 2020 and interviewed 17 young adults (age 18-21 years) who reviewed resources and provided their opinion on the resource's relevance for their age group. Interviews were stratified by vaping status, transcribed, coded, and thematically analyzed. Results: Only 5 of 10 EHR systems included prompts to capture information about vaping and data capture was optional in all 5 cases. Of the 17 interviewees, 10 were female, 14 were White, 3 were non-White and the mean age was 19.6 years. Two central themes emerged. Young adults: 1) were open to confidential, non-confrontational interactions with trusted providers and supported the use of a 2-page resource/discussion guide, questionnaires about vaping, and other waiting room resources, and 2) wanted prevention and cessation resources to be age-appropriate, including medical facts from a trusted source, and to be disseminated via social media platforms used by young adults. Conclusions: We found a lack of EHR functionalities in screening for vaping status hindered patients from receiving counseling on use. Young adults report a willingness to communicate with and learn from trusted providers and to gain understanding from information accessed via social media.

Management of Chordoma of the Sacrum and Mobile Spine.

➢: Chordomas account for 1% to 4% of primary tumors of the spine and sacrum. ➢: En bloc resection is the preferred surgical treatment for the management of chordomas. ➢: Proton beam radiation is increasingly being used as a postoperative radiation modality for the treatment of chordomas.

Pleiotropic Effects of Statins: New Therapeutic Approaches to Chronic, Recurrent Infection by Staphylococcus aureus.

An emergent approach to bacterial infection is the use of host rather than bacterial-directed strategies. This approach has the potential to improve efficacy in especially challenging infection settings, including chronic, recurrent infection due to intracellular pathogens. For nearly two decades, the pleiotropic effects of statin drugs have been examined for therapeutic usefulness beyond the treatment of hypercholesterolemia. Interest originated after retrospective studies reported decreases in the risk of death due to bacteremia or sepsis for those on a statin regimen. Although subsequent clinical trials have yielded mixed results and earlier findings have been questioned for biased study design, in vitro and in vivo studies have provided clear evidence of protective mechanisms that include immunomodulatory effects and the inhibition of host cell invasion. Ultimately, the benefits of statins in an infection setting appear to require attention to the underlying host response and to the timing of the dosage. From this examination of statin efficacy, additional novel host-directed strategies may produce adjunctive therapeutic approaches for the treatment of infection where traditional antimicrobial therapy continues to yield poor outcomes. This review focuses on the opportunistic pathogen, Staphylococcus aureus, as a proof of principle in examining the promise and limitations of statins in recalcitrant infection.

Clinical utilization of species-specific immunoassays for identification of Staphylococcus aureus and Streptococcus agalactiae in orthopedic infections.

Staphylococcus aureus and Streptococcus agalactiae (Group B streptococcus, GBS) are common causes of deep musculoskeletal infections (MSKI) and result in significant patient morbidity and cost to the healthcare system. One of the major challenges with MSKI is the lack of faithful diagnostics to correctly identify the primary pathogen, as standard culture-based assays are prone to false positives in the case of polymicrobial infections, and false negatives due to limitations in sample acquisition and antibiotic use before presentation. To improve upon our current diagnostic methods for MSKI, we developed a multiplex immunoassay for antigen-specific IgGs in serum (Luminex), and medium enriched for newly synthesized antibodies (MENSA) for anti-S. aureus and GBS generated from cultured peripheral blood mononuclear cells (PBMCs) of orthopedic infection patients undergoing surgical treatment. Samples were obtained from 110 MSKI patients: 80 diabetic foot ulcer, 21 periprosthetic joint infection, 5 septic arthritis, 2 spine, 1 hand, and 1 fracture-related infection (FRI). Anti-S. aureus and anti-GBS antibody titers were compared to culture results to assess their concordance in identifying the pathogens. Immunoassay, particularly MENSA, showed high diagnostic potential for monomicrobial S. aureus and GBS orthopedic infections (AUC > 0.95). MENSA also demonstrated diagnostic potential for GBS polymicrobial orthopedic infection and for GBS DFU (AUC > 0.83 for both). Serum showed high diagnostic potential for S. aureus PJI (AUC > 0.95). Taken together, these findings support the development of species-specific immunoassays for the identification of causal pathogens in active MSKI, especially in conjunction with standard culture.

Differential effects of cotreatment of the antibiotic rifampin with host-directed therapeutics in reducing intracellular Staphylococcus aureus infection.

BACKGROUND: Chronic infection by Staphylococcus aureus drives pathogenesis in important clinical settings, such as recurrent pulmonary infection in cystic fibrosis and relapsing infection in osteomyelitis. Treatment options for intracellular S. aureus infection are limited. Rifampin, a lipophilic antibiotic, readily penetrates host cell membranes, yet monotherapy is associated with rapid antibiotic resistance and development of severe adverse events. Antibiotic cotreatment can reduce this progression, yet efficacy diminishes as antibiotic resistance develops. ML141 and simvastatin inhibit S. aureus invasion through host-directed rather than bactericidal mechanisms. OBJECTIVE: To determine whether cotreatment of ML141 or of simvastatin with rifampin would enhance rifampin efficacy. METHODS: Assays to assess host cell invasion, host cell viability, host cell membrane permeability, and bactericidal activity were performed using the human embryonic kidney (HEK) 293-A cell line infected with S. aureus (29213) and treated with vehicle control, simvastatin, ML141, rifampin, or cotreatment of simvastatin or ML141 with rifampin. RESULTS: We found cotreatment of ML141 with rifampin reduced intracellular infection nearly 85% when compared to the no treatment control. This decrease more than doubled the average 40% reduction in response to rifampin monotherapy. In contrast, cotreatment of simvastatin with rifampin failed to improve rifampin efficacy. Also, in contrast to ML141, simvastatin increased propidium iodide (PI) positive cells, from an average of 10% in control HEK 293-A cells to nearly 20% in simvastatin-treated cells, indicating an increase in host cell membrane permeability. The simvastatin-induced increase was reversed to control levels by cotreatment of simvastatin with rifampin. CONCLUSION: Taken together, rifampin efficacy is increased through host-directed inhibition of S. aureus invasion by ML141, while efficacy is not increased by simvastatin. Considerations regarding novel therapeutic approaches may be dependent on underlying differences in pharmacology.

Scientific solution to a complex problem: physiology and multidisciplinary team improve understanding and outcome in chronic constipation and faecal incontinence.

PURPOSE: There is a lack of diagnostic credibility to direct focused management for children with chronic constipation (CC) and faecal incontinence (FI). The aim is to assess the impact of an innovative Children's Anorectal Physiology Service (CAPS) focusing on improving outcomes in children with CC/FI. METHODS: Prospective data: demographics, bowel and quality of life (QoL)/risk of distress questionnaires. Diagnostics: awake high-resolution anorectal manometry (AHRAM), endoanal ultrasound and transit marker studies (TMS). RESULTS: Total patients: 112; 66 males (59%); median 9 years (17 months to 16 years). Patient groups included: 89 (79%) had functional CC/FI; 9 (8%), Hirschsprung's disease; 12 (11%), anorectal malformations and 2 (2%), trauma. St Marks Incontinence score (SMIS) abnormal in 91 (81%) and Cleveland Constipation Score (CCS) in 101 (90%) patients. Anorectal manometry: 94 (84%) awake and 18 (17%) under anaesthesia. Play specialist input 37 (33%) patients. AHRAM abnormal 65 (58%): sphincter dysfunction 36 (32%) and altered rectal sensation: hyposensitive 22% (20/91); 21% (19/91) hypersensitive. TMS normal in 64 (57%), 17 (15%) slow transit and 27 (24%) rectal evacuatory disorder. Risk of distress in 38% and poor QoL in 55% patients which correlated with abnormal SMIS (p = 0.02). Patient/parent satisfaction improved significantly (p < 0.05). CONCLUSIONS: Scientific investigations combined with multidisciplinary team improve patient satisfaction and reduces patient self-report illness severity. A complex problem requires a scientific solution.

Simvastatin and ML141 Decrease Intracellular Streptococcus pyogenes Infection.

BACKGROUND: Recurrent pharyngotonsillitis due to Streptococcus pyogenes develops regardless of whether infecting strains are resistant or susceptible to first-line antimicrobials. Causation for recurrent infection is associated with the use of first-line antimicrobials that fail to penetrate deep tissue and host cell membranes, enabling intracellular S. pyogenes to survive throughout repeated rounds of antimicrobial therapy. OBJECTIVE: To determine whether simvastatin, a therapeutic approved for use in the treatment of hypercholesterolemia, and ML141, a first-in-class small molecule inhibitor with specificity for human CDC42, limit host cell invasion by S. pyogenes. METHODS: Assays to assess host cell invasion, bactericidal activity, host cell viability, actin depolymerization, and fibronectin binding were performed using the RAW 267.4 macrophage cell line and Human Umbilical Vein Endothelial Cells (HUVEC) infected with S. pyogenes (90-226) and treated with simvastatin, ML141, structural analogs of ML141, or vehicle control. RESULTS: Simvastatin and ML141 decreased intracellular infection by S. pyogenes in a dose-dependent manner. Inhibition by simvastatin persisted following 1 h washout whereas inhibition by ML141 was reversed. During S. pyogenes infection, actin stress fibers depolymerized in vehicle control treated cells, yet remained intact in simvastatin and in ML141 treated cells. Consistent with the previous characterization of ML141, simvastatin decreased host cell binding to fibronectin. Structural analogs of ML141, designated as the RSM series, decreased intracellular infection through non-cytotoxic, nonbactericidal mechanisms. CONCLUSION: Our findings demonstrate the potential of repurposing simvastatin and of developing CDC42-targeted therapeutics for eradicating intracellular S. pyogenes infection to break the cycle of recurrent infection through a host-directed approach.

Short Term, Low Dose Simvastatin Pretreatment Alters Memory Immune Function Following Secondary Staphylococcus aureus Infection.

Statins are potent modulators of immune responses, resulting in their ability to enhance host survival from primary bacterial infections. Alterations in primary immune responses that may be beneficial for survival following infection may also result in alterations in the generation of the immunologic memory response and subsequently affect immune responses mounted during secondary bacterial infection. In this study, we report that levels of total serum IgG2c, following primary infection, were decreased in simvastatin pretreated mice, and investigate the effect of simvastatin treatment, prior to primary infection, on immune responses activated during secondary S. aureus infection. A secondary infection model was implemented whereby simvastatin pretreated and control mice were reinfected with S. aureus 14 days after primary infection, with no additional simvastatin treatment, and assessed for survival and alterations in immune function. While survivability to secondary S. aureus infection was not different between simvastatin pretreated and control mice, memory B and T lymphocyte functions were altered. Memory B cells, isolated 14 days after secondary infection, from simvastatin pretreated mice and stimulated ex vivo produced increased levels of IgG1 compared to memory B cells isolated from control mice, while levels of IgM and IgG2c remained similar. Furthermore, memory B and T lymphocytes from simvastatin pretreated mice exhibited a decreased proliferative response when stimulated ex vivo compared to memory cells isolated from control mice. These findings demonstrate the ability of a short term, low dose simvastatin treatment to modulate memory immune function.

Transanal irrigation for intractable faecal incontinence and constipation: outcomes, quality of life and predicting non-adopters.

PURPOSE: Intractable faecal incontinence (FI) and constipation is a challenging condition to manage in children. Transanal irrigation (TAI) is a non-operative treatment option. This study presents our experience with TAI with the aim of finding predictive factors of non-compliance. METHODS: This is an outcome and quality of life (QoL) study of a prospectively maintained database of patients < 17 years old commenced on TAI for intractable FI/constipation between 2008 and 2014. Outcome measures were: (1) compliance-classified as non-adopter (use of TAI stopped within 1 month after commencement) or adopter; (2) functional outcome-classified as responder (totally continent or occasional soiling) or non-responder; (3) Rintala score; and (4) QoL score (PedsQL™ 4.0 Generic Core Scale). Analysis to determine predictive factors was also performed. RESULTS: 42 patients were started on TAI [74% male, median age of commencement was 7 (3-16) years]. Underlying diagnoses were: idiopathic constipation (62%), anorectal malformation (26%), Hirschsprung disease (5%), spina bifida (5%) and gastroschisis (2%). Median follow-up period was 14 (3-78) months. 24% were non-adopters. 84% of the adopters responded to treatment. Rintala scores (mean ± SD) pre- and post-TAI were 6.7 ± 3.5 and 11.2 ± 4.8, respectively (P < 0.001). QoL scores pre- and post-TAI were 55.6 ± 24.1 and 65.5 ± 23.7, respectively (P < 0.001). Median age at which TAI was commenced in the non-adopter and adopter group were 6 (IQR 4.5-8.25) and 8 (IQR 7-12), respectively (P = 0.008). CONCLUSION: TAI is a safe and effective treatment for intractable constipation/FI in children. If tolerated, it can significantly improve quality of life. Age and underlying diagnosis are important factors when recommending TAI to children with intractable FI/constipation.

Small Molecule Inhibitors Limit Endothelial Cell Invasion by Staphylococcus aureus.

Staphylococcus aureus is a leading causative agent in sepsis, endocarditis, and pneumonia. An emerging concept is that prognosis worsens when the infecting S. aureus strain has the capacity to not only colonize tissue as an extracellular pathogen, but to invade host cells and establish intracellular bacterial populations. In previous work, we identified host CDC42 as a central regulator of endothelial cell invasion by S. aureus. In the current work, we report that ML 141, a first-in-class CDC42 inhibitor, decreases invasion and resultant pathogenesis in a dose-dependent and reversible manner. Inhibition was found to be due in part to decreased remodeling of actin that potentially drives endocytic uptake of bacteria/fibronectin/integrin complexes. ML 141 decreased binding to fibronectin at these complexes, thereby limiting a key pathogenic mechanism used by S. aureus to invade. Structural analogs of ML 141 were synthesized (designated as the RSM series) and a subset identified that inhibit invasion through non-cytotoxic and non-bactericidal mechanisms. Our results support the development of adjunctive therapeutics targeting host CDC42 for mitigating invasive infection at the level of the host.

Enumeration of sublethally injured Escherichia coli O157:H7 ATCC 43895 and Escherichia coli strain B-41560 using selective agar overlays versus commercial methods.

Quality control procedures during food processing may involve direct inoculation of food samples onto appropriate selective media for subsequent enumeration. However, sublethally injured bacteria often fail to grow, enabling them to evade detection and intervention measures and ultimately threaten the health of consumers. This study compares traditional selective and nonselective agar-based overlays versus two commercial systems (Petrifilm and Easygel) for recovery of injured E. coli B-41560 and O157:H7 strains. Bacteria were propagated in tryptic soy broth (TSB), ground beef slurry, and infant milk formula to a density of 10(6) to 10(8) CFU/ml and then were stressed for 6 min either in lactic acid (pH 4.5) or heat shocked for 3 min at 60°C. Samples were pour plated in basal layers of either tryptic soy agar (TSA), sorbitol MacConkey agar (SMAC), or violet red bile agar (VRB) and were resuscitated for 4 h prior to addition of agar overlays. Other stressed bacteria were plated directly onto Petrifilm and Easygel. Results indicate that selective and nonselective agar overlays recovered significantly higher numbers (greater than 1 log) of acid- and heat-injured E. coli O157:H7 from TSB, ground beef, and infant milk formula compared with direct plating onto selective media, Petrifilm, or Easygel, while no significant differences among these media combinations were observed for stressed E. coli B-41560. Nonstressed bacteria from TSB and ground beef were also recovered at densities significantly higher in nonselective TSA-TSA and in VRB-VRB and SMAC-SMAC compared with Petrifilm and Easygel. These data underscore the need to implement food safety measures that address sublethally injured pathogens such as E. coli O157:H7 in order to avoid underestimation of true densities for target pathogens.

Host cell invasion by Staphylococcus aureus stimulates the shedding of microvesicles.

During severe sepsis, microvesicles that are positive for tissue factor (TF) are at increased levels within blood and in pulmonary lavage. These microvesicles potentially disperse TF, the major initiator of the coagulation cascade, throughout multiple organ systems, initiating fibrin deposition and resultant ischemia. The source of these microvesicles has remained incompletely defined. Although TF(+) microvesicles are shed from cells that express nascent TF transcript in response to injury, recent findings revealed that circulating, full-length TF protein is detectable prior to these nascent transcripts. This finding suggested that the protein is released from constitutive sources as an acute response. We examined whether Staphylococcus aureus, the Gram-positive bacteria that is emerging as one of the most common etiologic agents in sepsis, is capable of stimulating the release of TF(+) microvesicles from a pulmonary cell line that constitutively expresses TF protein. We found that host cell invasion stimulated an acute release of TF(+) microvesicles and that these microvesicles mediated the transfer of the protein to TF-negative endothelial cells. We also found that transfer was inhibited by cholesterol-lowering simvastatin. Taken together, our findings reveal that S. aureus pathogenesis extends to the acute release of TF(+) microvesicles and that inhibiting dispersal by this mechanism may provide a therapeutic target.

Short term statin treatment improves survival and differentially regulates macrophage-mediated responses to Staphylococcus aureus.

Staphylococcus aureus is the most prevalent etiologic agent of sepsis. Statins, primarily prescribed for their cholesterol-lowering capabilities, may be beneficial for treating sepsis due to their anti-inflammatory properties. This study examined the effect of low dose, short term simvastatin pretreatment in conjunction with antibiotic treatment on host survival and demonstrated that pretreatment with simvastatin increased survival of C57BL/6 mice in response to S. aureus infection. In vitro studies revealed that short term simvastatin pretreatment did not reduce S. aureus-stimulated expression of surface proteins necessary for macrophage presentation of antigen to T cells, such as MHC Class II and costimulatory molecules CD80 and CD86, but did reduce both basal and S. aureus-stimulated levels of C5aR. Additionally, this work demonstrated the ability of simvastatin to dampen macrophage responses initiated not only by bacteria directly but by membrane vesicles shed in response to infection, revealing a new mechanism of immune modulation by statins. These data demonstrate the ability of short term simvastatin pretreatment to modulate immune responses and identify new insights into the underlying mechanisms of the anti-inflammatory properties of simvastatin that may decrease the pathophysiological effects leading to sepsis.

Modified Ollier transtrochanteric approach for the treatment of acetabular fractures.

The purpose of this retrospective clinical study was to evaluate the rates of wound and neurologic complications and clinically significant heterotopic ossification, Brooker stage 3 and 4, with the modified Ollier transtrochanteric approach for the treatment of acetabular fractures. The study group comprised 94 consecutive patients (95 acetabuli) who had unstable acetabular fractures requiring surgical fixation. All patients were treated with open reduction internal fixation via the Ollier approach by a single surgeon (L.E.D.). Demographic and clinical information regarding rates of wound and neurologic complications and remaining articular stepoff at fixation was obtained from a chart review. The degree of heterotopic ossification was graded from standard anteroposterior pelvis radiographs according to the Brooker classification. Six (6%) patients underwent reoperation for infection; however, only 3 (3%) of these patients had deep infections. Three (3%) patients had iatrogenic sciatic nerve injuries; only 1 patient had persistent sensory changes at final follow-up. Thirteen (18%) of the 73 patients with radiographs available for review at a minimum of 3-month follow-up had Brooker grade III heterotopic ossification and 1 (1%) patient had grade IV. Five (5%) patients underwent excision of heterotopic ossification. Fourteen (17%) of 81 patients had no radiographic union of the greater trochanteric osteotomy, but none of these patients required further surgery. The complication rates of the Ollier approach in this study compare favorably with alternative surgical approaches reported in large series. We believe this approach provides excellent exposure without increasing the risk of complications.

Simvastatin is protective during Staphylococcus aureus pneumonia.

Epidemiologic studies suggest that the incidence and severity of sepsis are ameliorated in patients on statins (3- hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) for cholesterol lowering indications. We sought to understand the mechanism underlying such protection and hypothesized that simvastatin would be protective in mice against acute infection with Staphylococcus aureus, the primary etiologic agent in sepsis. Mice were treated with simvastatin or buffer for two weeks and were subsequently challenged with S. aureus intratracheally or intravenously. Relative to buffer-treated mice, bacterial killing was enhanced 4-fold (p=0.02), systemic dissemination was reduced, and lethality was decreased (hazard ratio 8.8, 95% CI 2.5 to 31.3, p=0.001) in mice that were pretreated with simvastatin for two weeks. Systemic inflammatory response was abrogated and the local elaboration of inflammatory mediators was diminished. Serum concentrations of pro-fibrinolytic protein C were elevated (p=0.034), while the concentration of pro-coagulant tissue factor in bronchoalveolar lavage fluids was attenuated (reduced 25%), p=0.001, in simvastatin-treated mice. Taken together, these data indicate that extended treatment with simvastatin is protective during infection with S. aureus through enhanced bacterial clearance, anti-inflammatory, and anti-coagulant activities. These studies provide insights into the mechanism by which statins confer protection in acute infection, support the notion that statins may be effective adjuncts in the treatment of sepsis, and provide a rationale for randomized control trials in patients that are at a high risk for infection characterized by coagulopathy.