Nephrotoxicity of Vancomycin in Combination With Beta-Lactam Agents: Ceftolozane-Tazobactam vs Piperacillin-Tazobactam.

BACKGROUND: Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP). METHODS: We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan-Meir analysis to assess the time to nephrotoxicity between the 2 groups. RESULTS: We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560-6.993). Results of the stratified Kaplan-Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001). CONCLUSIONS: Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T.

Implementation of indication-based antibiotic order sentences improves antibiotic use in emergency departments.

INTRODUCTION: Prior data have suggested that suboptimal antibiotic prescribing in the emergency department (ED) is common for uncomplicated lower respiratory tract infections (LRTI), urinary tract infections (UTI), and acute bacterial skin and skin structure infections (ABSSSI). The objective of this study was to measure the effect of indication-based antibiotic order sentences (AOS) on optimal antibiotic prescribing in the ED. METHODS: This was an IRB-approved quasi-experiment of adults prescribed antibiotics in EDs for uncomplicated LRTI, UTI, or ABSSSI from January to June 2019 (pre-implementation) and September to December 2021 (post-implementation). AOS implementation occurred in July 2021. AOS are lean process, electronic discharge prescriptions retrievable by name or indication within the discharge order field. The primary outcome was optimal prescribing, defined as correct antibiotic selection, dose, and duration per local and national guidelines. Descriptive and bivariate statistics were performed; multivariable logistic regression was used to determine variables associated with optimal prescribing. RESULTS: A total of 294 patients were included: 147 pre-group and 147 post-group. Overall optimal prescribing improved from 12 (8%) to 34 (23%) (P < 0.001). Individual components of optimal prescribing were optimal selection at 90 (61%) vs 117 (80%) (P < 0.001), optimal dose at 99 (67%) vs 115 (78%) (P = 0.036), and optimal duration at 38 (26%) vs 50 (34%) (P = 0.13) for pre- and post-group, respectively. AOS was independently associated with optimal prescribing after multivariable logistic regression analysis (adjOR, 3.6; 95%CI,1.7-7.2). A post-hoc analysis showed low uptake of AOS by ED prescribers. CONCLUSIONS: AOS are an efficient and promising strategy to enhance antimicrobial stewardship in the ED.

Impact of a Standardized, Pharmacist-Initiated "Test-Claim" Workflow for Anticipating Barriers to Accessing Discharge Antimicrobials.

Background: Inability to access and afford discharge oral antimicrobials may delay discharges or result in therapeutic failure. "Test-claims" have the potential to identify such barriers. Objective: This study evaluated discharge antimicrobial access and patient outcomes after implementation of a standardized, inpatient pharmacist-initiated antimicrobial discharge medication cost inquiry (aDMCI) process. Methods: This was an Institutional Review Board (IRB)-approved, pilot retrospective cohort study that included adults admitted for ≥72 hours from November 1, 2018, to February 28, 2019, and discharged on oral antimicrobials. Patients with a cost inquiry (aDMCI group) were compared with those without (standard-of-care, SOC, group). Primary endpoint was discharge delay. Secondary endpoints included percentage of patients discharged on suboptimal antimicrobials and medication errors from aDMCI. Results: 84 patients were included: 43 in SOC and 41 in aDMCI. Seventy-five antimicrobial cost inquiries were evaluated among 41 patients. There were no discharge delays or medication errors associated with the standardized "test-claim" (aDMCI) workflow. Patients in the SOC group had a greater Charlson Comorbidity Index (4 [2-6] vs 2 [1-4], P =0.004), were more likely to be immunosuppressed (24, 56% vs 12, 29%; P =0.014), and had longer hospitalization (8 [5-15] vs 6 [5-9] days, P =0.026). Primary access barriers were prior-authorization (8, 11%) and associated with linezolid and moxifloxacin cost inquiries. Most aDMCIs results were available in <24 hours (66, 88%). Conclusions: The aDMCI process is safe and offers an actionable transition of care tool that can identify barriers to accessing discharge medications while insulating patients from surprise out-of-pocket cost.

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Economic and social drivers of antibiotic dispensing practices among community pharmacies in Nepal.

OBJECTIVE: To assess economic and social drivers of dispensing antibiotics without prescription by community pharmacies in Nepal. METHOD: A survey was conducted among 111 pharmacy owners and managers in five districts. Information on demographic and economic characteristics of the pharmacies (e.g. revenue and profits from antibiotics) and their inclination to sell antibiotics without a physician's prescription under various scenarios (e.g. diarrhoea in a child) was collected. Univariate analysis was conducted to assess the demographic and economic characteristics. Bivariate analysis was conducted to examine the relationship between dispensing antibiotics without prescription and economic and social factors. RESULTS: Azithromycin and amoxicillin were the most commonly dispensed antibiotics. The proportions of pharmacies reporting that they would 'most likely' or 'likely' dispense antibiotics without prescription to adult patients ranged from 36.9% (sore throat) to 67.6% (cough). The proportions for paediatric patients ranged from 62.2% (sore throat) to 80.2% (cough or diarrhoea). There was no consistent relationship between the likelihood of dispensing antibiotics and revenues, profits or the number of patients. Instead, dispensing behaviour was influenced by the pressure from the patient; the respondents were more likely to dispense antibiotics when the patient specifically asked for 'an antibiotic' rather than for 'a medicine', and 68.5% respondents ranked 'customer satisfaction' as the most important factor motivating their work. CONCLUSIONS: In Nepal, inappropriate sale of antibiotics by community pharmacists is high, particularly for paediatric patients. Additional research is needed to establish key drivers of this behaviour and to help design effective approaches to reducing AMR.

High-Dose Daptomycin Is Well Tolerated via 2-Minute IV Push Administration.

BACKGROUND: The purpose of this study was to evaluate the safety of administering high-dose daptomycin (HDD; > 6 mg/kg actual body weight) as a 2-minute intravenous (IV) push (IVP) compared to traditional 30-minute IV piggyback (IVPB) infusion. METHODS: Retrospective cohort study comparing patients receiving HDD as an IVP or IVPB infusion. The primary outcome was the proportion of patients with a documented infusion-related reaction (IRR) to daptomycin. RESULTS: Three hundred patients were included in the final analysis, 200 patients received IVP, and 100 patients received IVPB representing a total of 1697 administrations. Median (IQR) daptomycin dose was IVP 700 mg (550-900) and IVPB 700 mg (600-900), with mg/kg doses of 8.2 (7.9-10) and 8.3 (8-10), respectively. After adjudication, IRR occurred in 1% of subjects in each treatment group. CONCLUSIONS: This study provides data in more than 1100 administrations of HDD administered via IVP. Infusion-related reactions were documented in 1% of patients regardless of infusion method, suggesting comparable safety to traditional infusion methods. This practice may be useful during fluid shortage and in the outpatient setting.

Discharge Delays and Costs Associated With Outpatient Parenteral Antimicrobial Therapy for High-Priced Antibiotics.

BACKGROUND: Outpatient parenteral antimicrobial therapy (OPAT) is a widely used, safe, and cost-effective treatment. Most public and private insurance providers require prior authorization (PA) for OPAT, yet the impact of the inpatient PA process is not known. Our aim was to characterize discharge barriers and PA delays associated with high-priced OPAT antibiotics. METHODS: This was an institutional review board-approved study of adult patients discharged with daptomycin, ceftaroline, ertapenem, and novel beta-lactam-beta-lactamase inhibitor combinations from January 2017 to December 2017. Patients with an OPAT PA delay were compared with patients without a delay. The primary endpoint was total direct hospital costs from the start of treatment. RESULTS: Two-hundred patients were included: 141 (71%) no OPAT delay vs 59 (30%) OPAT delay. More patients with a PA delay were discharged to a subacute care facility compared with an outpatient setting: 37 (63%) vs 52 (37%), P = .001. Discharge delays and median total direct hospital costs were higher for patients with OPAT delays: 31 (53%) vs 21 (15%), P < .001 and $19 576 (interquartile range [IQR], 10 056-37 038) vs $7770 (IQR, 3031-13 974), P < .001. In multiple variable regression, discharge to a subacute care facility was associated with an increased odds of discharge delay, age >64 years was associated with a decreased odds of discharge delay. CONCLUSIONS: OPAT with high-priced antibiotics requires significant care coordination. PA delays are common and contribute to discharge delays. OPAT transitions of care represent an opportunity to improve patient care and address access barriers.

Daptomycin Plus ß-Lactam Combination Therapy for Methicillin-resistant Staphylococcus aureus Bloodstream Infections: A Retrospective, Comparative Cohort Study.

BACKGROUND: Mounting evidence suggests the addition of a ß-lactam (BL) to daptomycin (DAP) results in synergistic in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) and bolsters the innate immune response to infection. This study's objective was to provide clinical translation to these experimental data and determine if DAP+BL combination therapy results in improved clinical outcomes compared with treatment with DAP alone in patients with MRSA bloodstream infections (BSIs). METHODS: This was a retrospective, comparative cohort study conducted at 2 academic medical centers between 2008 and 2018. Adults with MRSA BSI treated with DAP for ≥72 hours and initiated ≤5 days of culture collection were included. Patients who received a BL for ≥24 hours and initiated ≤24 hours of DAP comprised the DAP+BL group. The primary outcome was composite clinical failure (60-day all-cause mortality and/or 60-day recurrence). Analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW). RESULTS: A total of 229 patients were included (72 DAP+BL and 157 DAP). In unadjusted and IPTW-adjusted analyses, DAP+BL was associated with significantly reduced odds of clinical failure (odds ratio [OR], 0.362; 95% confidence interval [CI], .164-.801; adjusted OR, 0.386; 95% CI, .175-.853). Adjusted analyses restricted to prespecified subgroups based on infection complexity and baseline health status were consistent with the main analysis. CONCLUSIONS: The addition of a BL to DAP was associated with improved clinical outcomes in patients with MRSA BSI. This study provides support to ongoing and future studies evaluating the impact of combination therapy for invasive MRSA infections.Patients treated with daptomycin plus a ß-lactam for MRSA bloodstream infection had lower odds of composite clinical failure defined as 60-day all-cause mortality and/or 60-day recurrence compared with patients treated with daptomycin monotherapy after adjusting for confounding variables using inverse probability of treatment weighting.

Ceftolozane/Tazobactam vs Polymyxin or Aminoglycoside-based Regimens for the Treatment of Drug-resistant Pseudomonas aeruginosa.

BACKGROUND: Ceftolozane/tazobactam is a novel cephalosporin/beta-lactamase inhibitor combination that often retains activity against resistant Pseudomonas aeruginosa. The comparative safety and efficacy vs polymyxins or aminoglycosides in this setting remains unknown. METHODS: A retrospective, multicenter, observational cohort study was performed. Patients who received ceftolozane/tazobactam were compared with those treated with either polymyxin or aminoglycoside-based regimens for infections due to drug-resistant P. aeruginosa. Multivariate logistic regression was performed controlling for factors associated with treatment to assess the independent impact of ceftolozane/tazobactam on clinical cure, acute kidney injury (AKI), and in-hospital mortality. RESULTS: A total of 200 patients were included (100 in each treatment arm). The cohort represented an ill population with 69% in the intensive care unit, 63% mechanically ventilated, and 42% in severe sepsis or septic shock at infection onset. The most common infection type was ventilator-associated pneumonia (52%); 7% of patients were bacteremic. Combination therapy was more commonly used in polymyxin/aminoglycoside patients than those who received ceftolozane/tazobactam (72% vs 15%, P < .001). After adjusting for differences between groups, receipt of ceftolozane/tazobactam was independently associated with clinical cure (adjusted odds ratio [aOR], 2.63; 95% confidence interval [CI], 1.31-5.30) and protective against AKI (aOR, 0.08; 95% CI, 0.03-0.22). There was no difference in in-hospital mortality. The number needed to treat for a clinical cure with ceftolozane/tazobactam was 5, and the number needed to harm with AKI with a polymyxin/aminoglycoside was 4. CONCLUSIONS: These data support the preferential use of ceftolozane/tazobactam over polymyxins or aminoglycosides for drug-resistant P. aeruginosa infections.

Real-World Experience with Ceftolozane-Tazobactam for Multidrug-Resistant Gram-Negative Bacterial Infections.

Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and P. aeruginosa was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population (n = 226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio [aOR], 2.472 and 95% confidence interval [CI], 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ≥1 adverse effect (9 acute kidney injury, 13 Clostridioides difficile infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections.

Treatment and outcomes of Enterococcus faecium bloodstream infections in solid organ transplant recipients.

Optimal antimicrobial therapy for Enterococcus faecium bloodstream infection (EFBSI) in the solid organ transplant (SOT) population is not well defined. The purpose of this study was to describe the pharmacotherapy and outcomes of EFBSI in SOT patients. This was a single-center retrospective cohort of SOT patients with EFBSI from 2013 to 2019. Susceptibility testing was performed with Vitek® 2 or Etest. Estimates of optimal DAP pharmacokinetic/pharmacodynamic exposures (dose <10 mg/kg, fAUC/MIC >27.4) were made from previously established literature and equations. Fifty-one unique cases were included in the analysis. The median age was 61 years and liver (64%), intestinal (19%), and kidney (12%) were the most common organs transplanted. Most patients had indwelling central lines (75%) at the time of bacteremia; intra-abdominal abscesses/fluid collections were present in 44% of patients and 8% had endocarditis. Nineteen (37%) patients had polymicrobial infections. The most common definitive antimicrobial regimens were as follows: DAP plus beta-lactam (46%), DAP monotherapy (18%), and LZD (25%). Of the 33 patients that received DAP, 21% of E faecium isolates developed DAP resistance. 30-day mortality was 25% overall but higher in patients who received an initial DAP dose <10 mg/kg (43% vs 13%). Vancomycin-resistance, severity of illness, neutropenia, and source control were also associated with mortality. Inadequate DAP dosing for EFBSI may be associated with mortality in the SOT population. Larger, controlled analyses are necessary to determine the impact of optimized pharmacodynamics in this population.

Trends in and Predictors of Carbapenem Consumption across North American Hospitals: Results from a Multicenter Survey by the MAD-ID Research Network.

We sought to define trends in and predictors of carbapenem consumption across community, teaching, and university-affiliated hospitals in the United States and Canada. We conducted a retrospective multicenter survey of carbapenem and broad-spectrum noncarbapenem beta-lactam consumption between January 2011 and December 2013. Consumption was tabulated as defined daily doses (DDD) or as days of therapy (DOT) per 1,000 patient days (PD). Multivariate mixed-effects models were explored, and final model goodness of fit was assessed by regressions of observed versus predicted values and residual distributions. A total of 20 acute-care hospitals responded. The centers treated adult patients (n = 19/20) and pediatric/neonatal patients (n = 17/20). The majority of the centers were nonprofit (n = 17/20) and not affiliated with medical/teaching institutions (n = 11/20). The median (interquartile range [IQR]) carbapenem consumption rates were 38.8 (17.4 to 95.7) DDD/1,000 PD and 29.7 (19.2 to 40.1) DOT/1,000 PD overall. Carbapenem consumption was well described by a multivariate linear mixed-effects model (fixed effects, R2 = 0.792; fixed plus random effects, R2 = 0.974). Carbapenem consumption increased by 1.91-fold/quarter from 48.6 DDD/1,000 PD (P = 0.004) and by 0.056-fold/quarter from 45.7 DOT/1,000 PD (P = 0.93) over the study period. Noncarbapenem consumption was independently related to increasing carbapenem consumption (beta = 0.31 for increasing noncarbapenem beta-lactam consumption; P < 0.001). Regular antibiogram publication and promotion of conversion from intravenous (i.v.) to oral (p.o.) administration independently affected carbapenem consumption rates. In the final model, 58.5% of the observed variance in consumption was attributable to between-hospital differences. Rates of carbapenem consumption across 20 North American hospitals differed greatly, and the observed differences were correlated with hospital-specific demographics. Additional studies focusing on the drivers of hospital-specific carbapenem consumption are needed to determine whether these rates are justifiable.

Stewardship opportunities in viral pneumonia: Why not the immunocompromised?

Antimicrobial management of viral pneumonia has proven to be a challenge in hospitalized immunocompromised patients. A host of factors contribute to the dilemma, such as diagnostic uncertainty, lack of organism identification, and clinical status of the patient. Respiratory virus panel (RVP) use was compared between 131 immunocompromised patients who received send-out (n = 56) vs in-house (n = 75) testing. Antimicrobial optimization interventions consisted of antiviral addition/discontinuation, antibiotic discontinuation/de-escalation, or modification of immunosuppressive regimen. After implementation of an in-house test with audit and feedback, turnaround time of the RVP was reduced from 46.7 to 5.5 hours (P < .001) and time to intervention was reduced from 52.1 to 13.9 hours (P < .001), yet the frequency of antimicrobial optimization interventions was unchanged (30.7% vs 35.7%). Differences were not observed in duration of empiric antibiotic therapy or length of stay. The overall discontinuation rate for patients tested with a RVP was low (4.6%), and those with positive RVP (n = 43) had antibiotics stopped in 14% of cases. Bacterial pneumonia coinfection was confirmed in 2 patients. Further systematic efforts should be taken to reduce antibiotic use in viral pneumonia and identify the major barriers in the immunocompromised population.

Multicenter Observational Study of Ceftaroline Fosamil for Methicillin-Resistant Staphylococcus aureus Bloodstream Infections.

Novel therapies for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) are needed in the setting of reduced antibiotic susceptibilities and therapeutic failure. Ceftaroline is a cephalosporin antibiotic with MRSA activity. Although not FDA approved for MRSA BSI, ceftaroline has generated much interest as a potential treatment option. However, detailed descriptions of its use in this setting remain limited. To address this, we conducted a retrospective, multicenter, observational study of adult patients with MRSA BSI treated with at least 72 h of ceftaroline from 2011 to 2015. Safety outcomes were examined in the overall cohort, while efficacy outcomes were examined among patients who had not cleared their BSI prior to ceftaroline initiation. Data were also stratified by ceftaroline monotherapy or combination therapy. Predictors of clinical failure on ceftaroline treatment were also sought. Overall, 211 patients were included in the safety population; Clostridium difficile infection, rash, and neutropenia occurred in 6 patients (2.8%), 7 patients (3.3%), and 3 patients (1.4%), respectively. Clinical success was observed in 86 (68.3%) of the 126 patients included in the efficacy population. The monotherapy and combination therapy subgroups had similar proportions of patients experiencing success (69.7 and 64.9%, respectively). The median BSI durations post-ceftaroline treatment were 2 days (interquartile range, 1 to 4 days) for monotherapy and 3 days (interquartile range, 1.5 to 5 days) for combination therapy. Higher acute physiology and chronic health evaluation II scores and comorbid malignancy independently predicted treatment failure. Ceftaroline appears effective for MRSA BSI as both monotherapy and combination therapy. However, comparative studies are needed to further delineate the role of ceftaroline in MRSA BSI treatment.

Randomized Controlled Trial to Determine the Efficacy of Early Switch From Vancomycin to Vancomycin Alternatives as a Strategy to Prevent Nephrotoxicity in Patients With Multiple Risk Factors for Adverse Renal Outcomes (STOP-NT).

BACKGROUND: Use of alternative antimicrobials to vancomycin is a potential strategy to reduce acute kidney injury (AKI) in high-risk patients, but current data do not support widespread adoption of this practice. OBJECTIVE: To determine the efficacy of early switch to a nonnephrotoxic alternative for prevention of AKI in high-risk patients who receive vancomycin. METHODS: This was an IRB-approved, prospective randomized controlled trial in a single, tertiary care academic medical center. Patients initially prescribed vancomycin between October 2011 to April 2013 with at least 2 risk factors for AKI were included. Treatment randomization was stratified by indication for therapy. Patients were randomized to continuation of dose-optimized vancomycin or early switch to an alternative antimicrobial agent. The primary end point was nephrotoxicity by consensus guideline definition adjudicated by blinded review; the secondary end point was AKI network-defined AKI. RESULTS: A total of 103 patients were randomized; 100 were included in the modified intent-to-treat population, 51 in the vancomycin group and 49 in the alternative group. The incidence of nephrotoxicity was 6.1% in the alternative therapy arm and 9.8% in the vancomycin group ( P = 0.72). The incidence of AKI was 32.7% in the alternative therapy group and 31.4% in the vancomycin group ( P = 0.89). CONCLUSIONS: No significant difference in nephrotoxicity or AKI was detected among patients treated with alternative antimicrobials compared with vancomycin. The use of alternative antimicrobial therapy instead of vancomycin solely for the purpose of preventing AKI in high-risk patients does not appear to be warranted.

Time Is of the Essence: The Impact of Delayed Antibiotic Therapy on Patient Outcomes in Hospital-Onset Enterococcal Bloodstream Infections.

BACKGROUND: With increasing prevalence of vancomycin-resistant enterococci (VRE), appropriate antibiotic therapy for enterococcal bloodstream infections (EBSI) can be delayed. Data regarding the impact of delayed therapy on EBSI outcomes are conflicting, and the time delay most strongly associated with poor outcomes has not been defined. METHODS: This was a single-center, retrospective cohort study of adult, nonneutropenic patients with hospital-onset EBSI from 2010 to 2014. Classification and regression tree (CART) analysis was used to determine the delay in appropriate therapy most predictive of 30-day mortality. Appropriate therapy was defined as antibiotic therapy to which the enterococci and copathogen, where applicable, were susceptible. Outcomes and clinical characteristics were compared between patients receiving early or delayed therapy, defined by CART timepoint. Poisson regression was employed to determine the independent association of delayed therapy on 30-day mortality and predictors of delayed therapy. RESULTS: Overall, 190 patients were included. A breakpoint in time to appropriate therapy was identified at 48.1 hours, where 30-day mortality was substantially increased (14.6% vs 45.3%; P < .001). Patients receiving appropriate therapy after 48.1 hours also experienced higher in-hospital mortality and longer EBSI duration. After adjustment for severity of illness and comorbidity, delayed therapy ≥48.1 hours was associated with a 3-fold increase in 30-day mortality (risk ratio, 3.16 [95% confidence interval, 1.96-5.09]). Vancomycin resistance was the only independent predictor of delayed therapy. CONCLUSIONS: In patients with hospital-onset EBSI, receipt of appropriate therapy within the first 48 hours was associated with reduced mortality, underscoring the potential role of rapid diagnostic testing for early identification of VRE.

Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus: Does Vancomycin Heteroresistance Matter?

Vancomycin remains the mainstay treatment for methicillin-resistant Staphylococcus aureus (MRSA) infections, including pneumonia. There is concern regarding the emergence of vancomycin tolerance, caused by heterogeneous vancomycin-intermediate S. aureus (hVISA), and subsequent vancomycin treatment failure. Pneumonia is associated with high morbidity and mortality, especially with delays in appropriate therapy. This study evaluated the clinical outcomes of patients with hVISA pneumonia compared to those with vancomycin-susceptible S. aureus (VSSA) pneumonia. A retrospective cohort of patients with MRSA pneumonia from 2005 to 2014 was matched at a ratio of 2:1 VSSA to hVISA infections to compare patient characteristics, treatments, and outcomes. hVISA was determined by the 48-h population analysis profile area under the curve. Characteristics between VSSA and hVISA infections were compared by univariate analysis and multivariable logistic regression analysis to determine independent risk factors of inpatient mortality. Eighty-seven patients were included, representing 29 hVISA and 58 VSSA cases of pneumonia. There were no significant differences in demographics or baseline characteristics. Sequential organ failure assessment (SOFA) scores were a median of 7 (interquartile ratio [IQR], 5 to 8) in hVISA patients and 5 (IQR, 3 to 8) in VSSA (P = 0.092) patients. Inpatient mortality was significantly higher in hVISA patients (44.8% versus 24.1%; P = 0.049). Predictors of inpatient mortality upon multivariable regression were SOFA score (adjusted odds ratio [aOR], 1.36; 95% confidence interval [CI], 1.08 to 1.70), Panton-Valentine leukocidin (PVL) positivity (aOR, 6.63; 95% CI, 1.79 to 24.64), and hVISA phenotype (aOR, 3.95; 95% CI, 1.18 to 13.21). Patients with hVISA pneumonia experienced significantly higher inpatient mortality than those with VSSA pneumonia. There is a need to consider the presence of vancomycin heteroresistance in pneumonia caused by MRSA in order to potentially improve clinical outcomes.

Daptomycin Improves Outcomes Regardless of Vancomycin MIC in a Propensity-Matched Analysis of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections.

Vancomycin remains the mainstay treatment for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs) despite increased treatment failures. Daptomycin has been shown to improve clinical outcomes in patients with BSIs caused by MRSA isolates with vancomycin MICs of >1 mg/liter, but these studies relied on automated testing systems. We evaluated the outcomes of BSIs caused by MRSA isolates for which vancomycin MICs were determined by standard broth microdilution (BMD). A retrospective, matched cohort of patients with MRSA BSIs treated with vancomycin or daptomycin from January 2010 to March 2015 was completed. Patients were matched using propensity-adjusted logistic regression, which included age, Pitt bacteremia score, primary BSI source, and hospital of care. The primary endpoint was clinical failure, which was a composite endpoint of the following metrics: 30-day mortality, bacteremia with a duration of ≥7 days, or a change in anti-MRSA therapy due to persistent or worsening signs or symptoms. Secondary endpoints included MRSA-attributable mortality and the number of days of MRSA bacteremia. Independent predictors of failure were determined through conditional backwards-stepwise logistic regression with vancomycin BMD MIC forced into the model. A total of 262 patients were matched. Clinical failure was significantly higher in the vancomycin cohort than in the daptomycin cohort (45.0% versus 29.0%; P = 0.007). All-cause 30-day mortality was significantly higher in the vancomycin cohort (15.3% versus 6.1%; P = 0.024). These outcomes remained significant when stratified by vancomycin BMD MIC. There was no significant difference in the length of MRSA bacteremia. Variables independently associated with treatment failure included vancomycin therapy (adjusted odds ratio [aOR] = 2.16, 95% confidence interval [CI] = 1.24 to 3.76), intensive care unit admission (aOR = 2.46, 95% CI = 1.34 to 4.54), and infective endocarditis as the primary source (aOR = 2.33, 95% CI = 1.16 to 4.68). Treatment of MRSA BSIs with daptomycin was associated with reduced clinical failure and 30-day mortality; these findings were independent of vancomycin BMD MIC.

Outpatient use of ceftaroline fosamil versus vancomycin for osteoarticular infection: a matched cohort study.

OBJECTIVES: There are few convenient intravenous options for long-term outpatient treatment of osteoarticular infection (OAI) and limited effectiveness and safety data exist for this off-label use of ceftaroline. The objective of this study was to describe the long-term effectiveness and safety of ceftaroline for the treatment of OAI. METHODS: This was a matched retrospective cohort study of patients receiving ceftaroline- or vancomycin-based therapy for OAI in the outpatient setting. Patients were matched according to infection subtype, anatomical site and microbiology. The primary endpoint was 180 day infection-related readmission (IRR). Secondary endpoints included all-cause readmission, time-to-IRR and adverse event incidence. RESULTS: The final matched cohort consisted of 50 ceftaroline-treated patients and 50 vancomycin-treated patients. The IRR incidence was 22% for ceftaroline patients and 30% for vancomycin patients; OR = 0.66 (95% CI = 0.27-1.62; P = 0.362). There was no significant difference between groups in all-cause readmission or time-to-IRR. Attributable adverse event incidences were 24% and 18% for ceftaroline and vancomycin, respectively. Rash (10%) and nausea (6%) were the most common ceftaroline adverse events, while acute kidney injury (6%) and rash (4%) were the most common vancomycin adverse events. CONCLUSIONS: Attributable readmission and adverse events were common among patients treated with outpatient intravenous antimicrobials for OAI. This study found no appreciable difference in effectiveness or tolerability between ceftaroline- or vancomycin-treated patients. Although further research will be important to delineate the role of ceftaroline in the management of OAI, data derived from this study may aid clinicians in determining therapy when limited options exist.

Outcomes of Aminopenicillin Therapy for Vancomycin-Resistant Enterococcal Urinary Tract Infections.

Vancomycin-resistant urinary tract infections are often challenging to treat. This retrospective cohort study compared outcomes between patients treated for vancomycin-resistant enterococcal urinary tract infection with an aminopenicillin and those treated with a non-ß-lactam antibiotic. Inpatients treated with an enterococcus-active agent for their first symptomatic vancomycin-resistant enterococcal urinary tract infection between 1 January 2012 and 31 December 2013 were considered for inclusion. Patients with colonization, on hospice, or receiving comfort care only were excluded. The primary endpoint of clinical cure was defined as resolution of clinical symptoms, or symptom improvement to the extent that no additional antibacterial drug therapy was necessary, and lack of microbiologic persistence. Secondary endpoints of 30-day readmission or retreatment and 30-day all-cause mortality were also compared. A total of 316 urinary isolates were screened, and 61 patients with symptomatic urinary tract infection were included. Twenty (35%) of the 57 isolates tested were ampicillin susceptible. Thirty-one patients received an aminopenicillin, and 30 received a non-ß-lactam. Rates of clinical cure for aminopenicillin versus non-ß-lactam treatment were 26/31 (83.9%) and 22/30 (73.3%) (P = 0.315), respectively. Rates of 30-day readmission (6/31, or 19.4%, versus 9/30, or 30%, respectively; P = 0.334), 30-day retreatment (4/31, or 12.9%, versus 4/30, 13.3%, respectively; P = 0.960), and 30-day all-cause mortality (2/31, or 6.5%, versus 1/30, or 3.3%, respectively; P = 0.573) were also not significantly different between groups. Aminopenicillins may be a viable option for treating vancomycin-resistant urinary tract infection regardless of the organism's ampicillin susceptibility. Prospective validation with larger cohorts of patients should be considered.