Characteristics and Outcomes of US Veterans With Immunocompromised Conditions at High Risk of SARS-CoV-2 Infection With or Without Receipt of Oral Antiviral Agents.

OBJECTIVES: Molnupiravir and nirmatrelvir-ritonavir were the first oral antiviral agents to demonstrate reduced hospitalization or death in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but patients with immunocompromised conditions were not well-represented. The objective of this study was to characterize and compare the clinical outcomes of US veterans with immunocompromised conditions prescribed oral antivirals with those who did not receive oral antivirals for mild-to-moderate SARS-CoV-2 active infection. METHODS: This was a retrospective, observational, nationwide propensity-matched analysis of US veterans with immunocompromised conditions who developed documented SARS-CoV-2 infection. The primary outcome was the composite of any hospitalization or death within 30 days of diagnosis. Secondary outcomes included 30-day comparative rates of (1) any hospitalization, (2) death, (3) intensive care requirement, and (4) subset analyses of outcomes by oral antiviral used and vaccination status. RESULTS: The composite primary outcome was significantly lower in patients receiving oral antiviral therapy compared with those who did not (23/390 [5.9%] vs 57/390 [14.6%]; odds ratio, 0.37; 95% confidence interval, .22-.61). This difference was driven largely by fewer deaths in the oral antiviral group (1/390 [0.3%] vs 19/390 [4.9%]; odds ratio, 0.05; 95% confidence interval, .007-.38). There was no significant difference in rate of intensive care requirement. The composite outcome was improved in vaccinated patients (completing the first series or first booster dose) who received oral antiviral agents compared with those who did not receive oral antiviral agents. Compared with those prescribed nirmatrelvir-ritonavir, patients given molnupiravir were older, had a higher incidence of cautions/contraindications, greater prevalence of tobacco use, and more cardiovascular complications. CONCLUSIONS: Use of molnupiravir or nirmatrelvir-ritonavir was associated with lower incidences of hospitalization or death within 30 days of diagnosis in US veterans with immunocompromised conditions, regardless of vaccination status. These findings support the use of either oral antiviral in this patient population.

Clinical outcomes of fidaxomicin vs oral vancomycin in recurrent Clostridium difficile infection.

WHAT IS KNOWN AND OBJECTIVE: Recurrent Clostridium difficile infection (CDI) occurs after initial treatment in approximately 20%-30% of patients, regardless of therapy chosen. The objective of this study was to assess clinical outcomes of recurrent CDI treated with fidaxomicin or oral vancomycin. METHODS: This study was a retrospective, propensity score-matched nationwide analysis of adult patients with first or second CDI recurrence prescribed fidaxomicin or oral vancomycin from any Veterans Affairs Medical Center between June 2011 and December 2015. The primary outcome was evidence of clinical failure or 90-day recurrence. RESULTS AND DISCUSSION: Univariate variables associated with failure or recurrence were identified among 65 fidaxomicin-treated episodes and 1065 vancomycin-treated episodes and placed into a multivariable logistic regression model. Propensity scores were calculated from this model; 195 vancomycin-treated episodes were matched by the next-nearest propensity score to 65 fidaxomicin-treated episodes. CDI failure or recurrence was similar between the two groups (18 of 65 [27.7%] fidaxomicin-treated episodes vs 42 of 195 [21.5%] vancomycin-treated episodes [P = 0.31]). Multivariate analysis demonstrated only baseline second recurrence episode, not choice of drug, as independently associated with failure or recurrence. WHAT IS NEW AND CONCLUSION: There was no difference in the combined outcome of clinical failure or 90-day recurrence between fidaxomicin and oral vancomycin in the treatment of first or second recurrent CDI.

An evaluation of hyperkalemia and serum creatinine elevation associated with different dosage levels of outpatient trimethoprim-sulfamethoxazole with and without concomitant medications.

BACKGROUND: Adverse events associated with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) for outpatient infections, particularly those likely caused by community-acquired methicillin-resistant Staphylococcus aureus, have not been adequately characterized. OBJECTIVE: Describe hyperkalemia and acute renal injury associated with high-dose TMP-SMX. METHODS: An electronic medical record database retrospective study was conducted of outpatients receiving high-dose or low-dose TMP-SMX, comparing the incidences of hyperkalemia and acute renal injury. RESULTS: Of 6162 patients, more developed hyperkalemia (3.06% vs 1.05%, P < .0001) or acute renal injury (1.99% vs 0.700%, P = .0001) in the high-dose TMP-SMX group. Variables independently associated with hyperkalemia included age >58 years (odds ratio [OR] = 3.44; 95% CI = 1.86-7.0; P < .0001), concomitant receipt of an NSAID (OR = 1.71; 95% CI = 1.02-2.79; P = .044) or an ACE inhibitor (OR = 3.27; 95% CI = 2.06-5.14; P < .0001), high-dose TMP-SMX prescribed (OR = 2.92; 95% CI = 1.85-4.60; P < .0001), and baseline elevated serum creatinine (OR = 45.1; 95% CI = 21.7-93.2; P < .0001). Variables independently associated with acute renal injury included concomitant receipt of an ACE inhibitor (OR = 2.36; 95% CI = 1.01-5.24; P = .048) or a potassium supplement (OR = 4.10; 95% CI = 1.45-10.1; P = .010), high-dose TMP-SMX prescribed (OR = 3.70; 95% CI = 1.70-8.12; P = .0012), and baseline elevated serum creatinine (OR = 2110; 95% CI = 724-7980; P < .0001). CONCLUSIONS: Serum creatinine and potassium concentrations should be monitored in outpatients receiving high-dose TMP-SMX.

Outcomes of health care-associated pneumonia empirically treated with guideline-concordant regimens versus community-acquired pneumonia guideline-concordant regimens for patients admitted to acute care wards from home.

BACKGROUND: The introduction of the health care-associated pneumonia (HCAP) categorization expanded recommendations for broad-spectrum empiric antibiotics to pneumonia patients presenting from the community with recent health care-system exposure. However, the efficacy of such regimens in improving clinical outcomes in these patients has not been well established. OBJECTIVE: To compare the clinical outcomes of HCAP patients treated initially with HCAP guideline-concordant antibiotic regimens to those treated initially with community-acquired pneumonia (CAP) guideline-concordant antibiotic regimens. METHODS: This retrospective study included HCAP patients presenting from home and admitted to general medical wards. HCAP regimen patients were treated empirically with at least 1 antipseudomonal agent. All other patients were assigned to the CAP regimen group. The primary end point was clinical cure at 30 days postdischarge. Subgroup analysis was performed in patients hospitalized 1-30 days and 31-90 days before the HCAP admission. RESULTS: Of 228 HCAP admissions, 122 patients received CAP regimens and 106 received HCAP regimens. The 2 groups were similar at baseline, including Pneumonia Severity Index scores. Attributable clinical cure occurred in 75.4% of CAP regimen patients and 69.8% of HCAP regimen patients (p = 0.34). Overall clinical cure occurred in 59.8% of CAP regimen patients and 54.7% of HCAP regimen patients (p = 0.44). The CAP regimen group used fewer days of intravenous antibiotics (4.39 vs 7.75, p < 0.0001) and had shorter lengths of stay (6.36 vs 8.58 days, p < 0.0001). For patients hospitalized 31-90 days earlier, clinical cure was higher in the CAP regimen group (attributable, 82.9% vs 60.0%, p = 0.0090; overall, 67.1% vs 47.5%, p = 0.044). CONCLUSIONS: Compared to CAP guideline-concordant regimens, treatment of HCAP with HCAP guideline-concordant regimens did not increase clinical cure rates and was associated with lower clinical cure rates in patients hospitalized 31-90 days prior to the HCAP admission. This study suggests that broad-spectrum empiric antibiotics may not be necessary in all HCAP patient groups.

Characteristics and outcomes of US Veterans at least 65 years of age at high risk of severe SARS-CoV-2 infection with or without receipt of oral antiviral agents.

OBJECTIVES: Molnupiravir and nirmatrelvir/ritonavir each became available in the United States (US) through the Food and Drug Administration (FDA) emergency use authorization (EUA) in December 2021 after their respective initial prospective randomized controlled trials demonstrated efficacy for patients with mild-to-moderate SARS-CoV-2 active infection considered to be at high risk for progression of disease and hospitalization. Although sufficiently powered for this wide group, the mean age for patients in these studies was only 43 and 46 years of age, respectively. We sought to compare outcomes of US Veterans 65 years and older who received either of these oral antivirals to those who did not receive oral antivirals for mild-to-moderate SARS-CoV-2 active infection. METHODS: The current project was a retrospective, observational, nationwide propensity-matched analysis comparing outcomes of US Veterans 65 years and older who received either of these oral antivirals to US Veterans 65 years and older who did not receive oral antivirals for mild-to-moderate SARS-CoV-2 active infection. RESULTS: The composite primary outcome of admission or death within 30 days of diagnosis was reached less often in those receiving either molnupiravir or nirmatrelvir/ritonavir versus those that received no antiviral (65/1370 [4.75%] vs. 139/1370 [10.2%]; odds ratio 0.44, 95% confidence interval 0.32-0.60, p<0.0001). Baseline differences between Veterans selected for molnupiravir vs. nirmatrelvir/ritonavir therapy were noted, particularly in the number of concomitant medications with cautions or contraindications with nirmatrelvir/ritonavir. CONCLUSIONS: Our findings support the use of molnupiravir or nirmatrelvir/ritonavir in patients 65 years of age and older. Patients with higher medication caution and contraindication burdens to nirmatrelvir/ritonavir are selected for molnupiravir therapy, which in the absence of a prospective head-to-head trial, may limit any efforts to compare the effectiveness of the two drugs.

Staphylococcus aureus bacteraemia treatment outcomes in patients receiving ticagrelor vs a propensity-matched cohort receiving clopidogrel.

OBJECTIVES: Ticagrelor may improve the outcomes in Staphylococcus aureus bacteraemia (SAB). However, treatment outcome data for these patients remain limited. The primary objective of this study was to characterize the outcomes of patients with SAB who received ticagrelor compared with a cohort who received clopidogrel. METHODS: This was a retrospective, nationwide propensity-matched analysis of patients with SAB who were prescribed ticagrelor or clopidogrel concomitantly with antistaphylococcal therapy. The primary outcome was the comparative all-cause 30-day mortality rate between propensity-matched groups. RESULTS: In total, 1509 patients were prescribed concomitantly with ticagrelor or clopidogrel during treatment of S. aureus bacteraemia; of these, 194 patients were excluded from this study due to an inadequate number of antiplatelet doses within the first week of therapy (n=171) or non-admission to hospital (n=23). Of the remaining 1315 patients, 74 patients received ticagrelor and 1241 patients received clopidogrel. There was no significant difference in all-cause 30-day mortality between the groups [6/74 (8.1%) in the ticagrelor group vs 10/74 (13.5%) in the clopidogrel group; P=0.29]. Multi-variate logistic regression demonstrated that elevated aspartate aminotransferase, systolic blood pressure <90 mmHg, elevated serum creatinine and neurological comorbidity were independently associated with all-cause 30-day mortality. CONCLUSIONS: This study found no difference in all-cause 30-day mortality between the two groups, although overall mortality appeared to be lower compared with other reports. Randomized controlled trials of P2Y12 inhibitors as adjunctive agents to antibiotic therapy for the treatment of serious S. aureus infections are warranted.

Propensity-matched analysis of the protective effect of ticagrelor versus clopidogrel on the risk of developing Staphylococcus aureus bacteremia.

OBJECTIVE: Recent data indicate that ticagrelor, used in acute coronary syndromes (ACS), has antibacterial effects against Staphylococcus sp. and other effects that may help management of infection. The primary objective of this study was to evaluate the protective effect of ticagrelor in patients who have had an ACS event and the risk of developing Staphylococcus aureus bacteremia (SAB) compared to a propensity-matched cohort receiving clopidogrel. METHODS: This study was a retrospective, nationwide analysis of all patients presenting to any percutaneous coronary intervention-performing Veterans Affairs Medical Center with an ACS episode and resultant prescription for clopidogrel or ticagrelor. The primary outcome was the comparative rate of SAB in patients receiving ticagrelor vs. clopidogrel. RESULTS: Analysis involved 24 456 patients on ticagrelor and 277 277 patients on clopidogrel. There was a statistically significant difference in the number of patients developing SAB between the propensity-matched groups (32 [0.13%] of 24 456 for ticagrelor vs. 71 [0.29%] of 24 456 for clopidogrel; odds ratio (OR), 0.43; 95% confidence interval (CI), 0.28-0.65; P<0.0001). Multivariate logistic regression showed that receipt of clopidogrel, comorbid dermatologic condition, comorbid hematologic condition, and baseline anemia were independently associated with the development of SAB. CONCLUSIONS: The study findings align with recent reports that ticagrelor may have a beneficial role in the prevention of SAB.

Development of SARS-CoV-2 infection in patients with rheumatic conditions on hydroxychloroquine monotherapy vs. patients without rheumatic conditions: A retrospective, propensity-matched cohort study.

BACKGROUND: The primary purpose of the current study was to examine whether patients with rheumatologic conditions receiving only chronic hydroxychloroquine therapy for their disease are at less risk of developing SARS-CoV-2 infection than a comparative group of patients without rheumatologic conditions. METHODS: A retrospective, observational, nationwide stratified propensity analysis was conducted comparing patients only on chronic treatment with hydroxychloroquine for their rheumatologic condition to a random sample of patients without rheumatologic conditions and not receiving hydroxychloroquine, utilizing a Veterans Health Administration nationwide clinical administrative database. RESULTS: The 1-to-1 stratified propensity analysis was undertaken using a random sample of patients without rheumatoid conditions and not receiving hydroxychloroquine (n  33,081) and patients with rheumatoid conditions receiving hydroxychloroquine as the lone medication for their condition (n  6047). A total of 5,474 patients in each group were successfully matched. The incidence of documented SARS-CoV-2 infections during the study period did not differ between patients receiving hydroxychloroquine and patients not receiving hydroxychloroquine (41/5,474 [0.749%] vs. 36/5,474 [0.658%], respectively, p = 0.57; Odds ratio [OR] 1.14, 95% confidence interval [CI] 0.73-1.79). There were no statistically-significant differences in secondary outcomes between the two groups in patients who developed active SARS-CoV-2 infection. Multivariate logistic regression to determine independent variables associated with the development of active SARS-CoV-2 infection failed to include receipt of hydroxychloroquine (OR 0.99, 95% CI 0.62-1.56). CONCLUSIONS: Hydroxychloroquine failed to demonstrate a preventative effect against SARS-CoV-2 infection in a large group of patients with rheumatologic conditions compared to patients without rheumatologic conditions.

Case-control study of statin prevention of mould infections.

Invasive mould infections (IMI) are associated with significant morbidity and mortality. In vitro studies have demonstrated that hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have activity against several pathogenic moulds including Zygomycetes and Aspergillus spp. The aim of our study was to determine if statin use is a preventive factor for the development of IMI. This was a retrospective case-control study of 10 United States Veterans Affairs Medical Centers that comprise the Veterans Integrated Service Network (VISN) 16. Cases with IMI and controls were identified from 2001 to 2008. Controls were matched by age, facility, history of transplantation, presence of chronic steroid use and presence of human immunodeficiency virus infection (HIV). Two hundred and thirty-eight patients were included. Independent variables associated with the development of IMI were history of solid malignant tumours (OR 2.63, 1.41-4.87) and hypertension (OR 2.29, 1.13-4.68). Statin use within 3 months of index date was not an independent variable for prevention or development of IMI. No level of exposure to a statin drug appeared to influence the development of infection. This retrospective case-control study suggests that despite evidence of in vitro activity, statins may not decrease risk of IMI. Prospective, controlled trials may be necessary to investigate any potential clinical benefit.

Continued decline in the prevalence of the Clostridioides difficile BI/NAP1/027 strain across the United States Veterans Health Administration.

In 2018, we demonstrated a decreased prevalence of the hypervirulent Clostridioides difficile BI/NAP1/027 strain across the United States (US) Veterans Health Administration (VHA) from 2011 through 2016. The objective of this retrospective study was to update the prevalence of the BI/NAP1/027 strain within the VHA from 2017 through 2020. Patients with positive tests for the presence of toxigenic C. difficile at any Veterans Affairs Medical Center found to also routinely test for BI/NAP1/027 strain presence were included between July 1, 2016 and June 30, 2020. In total, 7490 patients had 8148 positive C. difficile tests that had a corresponding BI/NAP1/027 test. Of those, there were 1031 (12.6%) presumptive positive tests for the BI/NAP1/027 strain. The overall prevalence of BI/NAP1/027 decreased from a high of 15.4% in 2017 to 8.21% in 2020. Statistically significant reductions in rates from 2017 to 2020 occurred in 4 of 9 US Census Bureau regions.

Outcomes associated with recent guideline recommendations removing metronidazole for treatment of non-severe Clostridioides difficile infection: a retrospective, observational, nationwide cohort study.

OBJECTIVES: The 2017 Society for Healthcare Epidemiology of America (SHEA) and Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for Clostridioides difficile (C. difficile) infection (CDI) removed metronidazole as a preferred option for initial episodes of non-severe CDI. This study aimed to determine if the shift away from metronidazole improved clinical outcomes of initial episodes of non-severe CDI. METHODS: The study was a retrospective, observational, nationwide cohort study using a Veterans Health Administration national clinical administrative database. Adult patients treated for non-severe CDI before and after the February 2018 publication of the 2017 IDSA/SHEA C. difficile Clinical Practice Guidelines were included. The primary outcome was the composite of treatment failure or probable recurrence. RESULTS: A total of 3608 patients were included, with 1809 in the pre-guideline cohort (mean [SD] age, 65.5 [14.2] years; 1602 [88.6%] male) and 1799 in the post-guideline cohort (mean [SD] age, 64 [14.6] years; 1584 [88%] male). Overall composite of treatment failure or probable recurrence was similar between both cohorts (318 of 1809 [17.6%] pre-guideline cohort vs. 317 of 1799 [17.6%] post-guideline cohort [P = 0.97]). CONCLUSION: The shift away from metronidazole as a preferred option in initial non-severe Clostridioides difficile infection did not improve the composite of treatment failure or recurrence.

The Effect of Nomenclature Revision of Streptococcus bovis to Streptococcus gallolyticus on Subsequent Colon Cancer Screening.

BACKGROUND: Lack of awareness of the taxonomic revision from the familiar Streptococcus bovis to the less familiar Streptococcus gallolyticus may be associated with a decrease in recommended colon cancer screening in patients with bacteremia from this organism. This could subsequently lead to a delay in diagnosis or underdiagnosis of colon cancer and other serious underlying gastrointestinal diseases. The aim of this study was to determine whether the nomenclature change of S. bovis to S. gallolyticus resulted in decreased colon cancer screening. METHODS: This study was a retrospective, observational, nationwide analysis of patients who had positive blood cultures for S. bovis/S. gallolyticus from any Veterans Affairs Medical Center (VAMC) between January 1, 2002, and December 31, 2017. RESULTS: There was no difference in the primary end point of intent for colonoscopy between the S. gallolyticus and S. bovis groups (66.5% [117/176] vs 62.1% [624/1005], respectively; P = .26). The overall mortality rate was 33.8% among 1181 patients included in the study, with a significantly lower mortality in patients with evidence of intent for colonoscopy (29.6% vs 42.5%; P ≤ .001), gastroenterology (GI) consultation (29.8% vs 41.4%; P < .001), infectious diseases (ID) consultation (29.4% vs 39.0%; P = .001), or either consultation (31.9% vs 40.7%; P = .013), compared to those that did not. CONCLUSIONS: There was no difference in colon cancer screening rates between patients with episodes of bacteremia reported as S. bovis and those reported as S. gallolyticus. Overall mortality was lower in patients who had ID consultation, GI consultation, or evidence of colonoscopy.

Long-term hydroxychloroquine use in patients with rheumatic conditions and development of SARS-CoV-2 infection: a retrospective cohort study.

BACKGROUND: Hydroxychloroquine is one of several agents being evaluated in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to examine whether patients with rheumatological conditions receiving chronic hydroxychloroquine therapy are at less risk of developing SARS-CoV-2 infection than those not receiving hydroxychloroquine. METHODS: This retrospective cohort study included de-identified information of all veterans in the US Veterans Health Administration clinical administrative database aged 18 years or older with rheumatoid arthritis, systemic lupus erythematosus, or associated rheumatological conditions (based on International Classification of Diseases, 10th edition, diagnostic codes) who were alive on March 1, 2020. A propensity score was calculated for each patient, and each patient who was receiving hydroxychloroquine was matched to two patients who were not receiving hydroxychloroquine (controls). The primary endpoint was the proportion of patients with PCR-confirmed SARS-CoV-2 infection among those receiving chronic hydroxychloroquine versus the propensity-matched patients not receiving chronic hydroxychloroquine between March 1 and June 30, 2020. Secondary outcomes were hospital admission associated with SARS-CoV-2 infection; intensive care requirement associated with SARS-CoV-2 infection; mortality associated with SARS-CoV-2 infection; and overall rates of any hospital admission and mortality (ie, all cause). Multivariate logistic regression analysis was done to determine independent variables for the development of active SARS-CoV-2 infection. FINDINGS: Between March 1 and June 30, 2020, 10 703 patients receiving hydroxychloroquine and 21 406 patients not receiving hydroxychloroquine were included in the primary analysis. The incidence of active SARS-CoV-2 infections during the study period did not differ between patients receiving hydroxychloroquine and patients not receiving hydroxychloroquine (31 [0·3%] of 10 703 vs 78 [0·4%] of 21 406; odds ratio 0·79, 95% CI 0·52-1·20, p=0·27). There were no significant differences in secondary outcomes between the two groups in patients who developed active SARS-CoV-2 infection. For all patients in the study, overall mortality was lower in the hydroxychloroquine group than in the group of patients who did not receive hydroxychloroquine (odds ratio 0·70, 95% CI 0·55-0·89, p=0·0031). In multivariate logistic regression analysis, receipt of hydroxychloroquine was not associated with the development of active SARS-CoV-2 infection (odds ratio 0·79, 95% CI 0·51-1·42). INTERPRETATION: Hydroxychloroquine was not associated with a preventive effect against SARS-CoV-2 infection in a large group of patients with rheumatological conditions. FUNDING: None.

Adverse outcomes associated with the use of drotrecogin alfa (activated) in patients with severe sepsis and baseline bleeding precautions.

BACKGROUND: Key clinical trials involving drotrecogin alfa (activated) (or recombinant human activated protein C) excluded patients with specific baseline bleeding precautions. However, not all such precautions are considered contraindications to treatment with recombinant human activated protein C in current product labeling. OBJECTIVE: To compare outcomes of patients receiving recombinant human activated protein C with or without baseline bleeding precautions as defined by the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. DESIGN: Retrospective medical record review. SETTING: Two tertiary care institutions: An academic medical center and an affiliated Veterans Affairs Medical Center. PATIENTS: All patients receiving recombinant human activated protein C for treatment of sepsis. INTERVENTIONS: Demographic information, characteristics associated with inclusion and exclusion criteria of the PROWESS trial, and 30-day postdischarge outcomes. MEASUREMENTS AND MAIN RESULTS: Seventy-three patients received recombinant human activated protein C. Serious bleeding events occurred in 7 of 20 patients (35%) with any baseline bleeding precaution vs. only 2 of 53 patients (3.8%) without any bleeding precautions (p < 0.0001). More patients with a baseline bleeding precaution died compared with patients without any bleeding precautions (65% vs. 24.5%, p = 0.0015). Patients with a baseline bleeding precaution had a higher mean Acute Physiology and Chronic Health Evaluation II score (27.5 vs. 22.7, p = 0.015). Multivariate analysis demonstrated that the presence of a baseline bleeding precaution was the only independent variable associated with occurrence of serious bleeding events. The presence of a baseline bleeding precaution, increased Acute Physiology and Chronic Health Evaluation II score, and the presence of bloodstream infection were independent variables associated with mortality. CONCLUSIONS: Patients with severe sepsis who received recombinant human activated protein C with baseline bleeding precautions as defined by product labeling had significantly higher rates of both serious bleeding events and deaths compared with those without bleeding precautions. These data suggest that strict adherence to PROWESS trial exclusion criteria would further limit serious bleeding events associated with the use of recombinant human activated protein C.

Part XIII. Systemic antifungal therapy.

Until the last decade of the 20th century, intravenous amphotericin B deoxycholate was the only agent available to treat the relatively rare occurrence of serious systemic fungal infections. In response to an explosion in the incidence of systemic fungal infections, within a 15 year period, four new classes of antifungal agents were introduced: the triazoles, liposomal amphotericin B preparations, an allylamine, and echinocandins (Table 1). So an updated review of antifungal therapy is in order.

A propensity score-matched analysis of the impact of minimum inhibitory concentration on mortality in patients with Pseudomonas aeruginosa bacteraemia treated with piperacillin/tazobactam.

The Clinical and Laboratory Standards Institute (CLSI) recently re-examined Pseudomonas aeruginosa minimum inhibitory concentration (MIC) susceptibility breakpoints for piperacillin/tazobactam (TZP). The objectives of this study were to analyse the impact of elevated TZP MICs (32-64 mg/L) versus lower respective MICs on P. aeruginosa bacteraemia patient outcomes. Data were gathered from a Veterans Health Administration national clinical database on P. aeruginosa bacteraemia episodes from 2007 to 2013. Patients treated with TZP were identified, comprising 53 elevated MIC episodes and 301 low MIC episodes. Propensity score matching (1:2 ratio) utilising independent variables associated with 30-day all-cause mortality was conducted to compare the outcomes of 53 elevated MIC episodes with 106 matched low MIC episodes. Independent baseline variables associated with 30-day all-cause mortality for all 354 episodes were hyperkalaemia, elevated blood urea nitrogen, elevated temperature, hypoglycaemia, lack of urinary source and thrombocytopenia. Similar 30-day all-cause mortality was found between the two propensity-matched TZP groups (elevated MIC 24.5% vs. low MIC 22.6%; P = 0.79).

A propensity score-matched analysis of the impact of minimum inhibitory concentration on mortality in patients with Pseudomonas aeruginosa bacteremia treated with cefepime or ceftazidime.

The United States Clinical and Laboratory Standards Institute recently elected not to revise ceftazidime and cefepime Pseudomonas aeruginosa minimum inhibitory concentration (MIC) susceptibility breakpoints but rather recommended specific dosage regimens to correspond to breakpoints. This study's objective was to examine mortality of low and high MIC P. aeruginosa isolates in bacteremic patients treated with cefepime or ceftazidime. Data were gathered through a Veterans Health Administration national administrative database for veterans with P. aeruginosa blood cultures who received cefepime or ceftazidime. Seventy-four patients in the low MIC (≤2 µg/mL) group and 29 patients in the high (4-8 µg/mL) MIC group were included. Independent baseline variables associated with 30-day all-cause mortality were determined through multivariate analysis to calculate propensity scores and perform matching. All-cause 30-day mortality was not statistically significant between the 2 resultant propensity score-matched groups (17.2% mortality in the low MIC group versus 27.6% in the high MIC group; P=0.34). Data suggested that P. aeruginosa bacteremia episodes where the cephalosporin MIC = 8 µg/mL may have higher mortality, however this may be reflective of higher propensity scores. Our study suggests that it is reasonable to designate a cefepime or ceftazidime MIC ≤8 µg/mL as susceptible for P. aeruginosa bacteremia infections, but potential suboptimal outcomes in episodes for which the P. aeruginosa MIC is 8 µg/mL may need further investigation.

A Propensity-Matched Analysis Between Standard Versus Tapered Oral Vancomycin Courses for the Management of Recurrent Clostridium difficile Infection.

BACKGROUND: This study was conducted to compare clinical outcomes of oral vancomycin courses without taper versus oral vancomycin courses with taper for treatment of recurrent Clostridium difficile infection (CDI). METHODS: This investigation was a multicenter, retrospective, propensity score-matched analysis study using a Veterans Health Administration national clinical administrative database. Adult patients who were treated for recurrent CDI from any Veterans Affairs Medical Center between June 1, 2011 and October 31, 2016 were included if they were treated with oral vancomycin with or without a tapering regimen. The 2 groups were matched by next-nearest approach from a propensity score formula derived from independent variables associated with the selection of a taper regimen. RESULTS: Propensity score matching resulted in 2 well-matched groups consisting of 226 episodes of patients treated with a vancomycin taper regimen and 678 episodes treated by vancomycin regimen without taper. No difference was found for the primary outcome of 180-day recurrence (59 of 226 [26.1%] for taper regimens versus 161 of 678 [23.8%], P = .48). A secondary outcome of 90-day all-cause mortality met statistical significance, favoring a taper regimen (5.31% vs 9.29%, P = .049); however, secondary outcomes of 90-day recurrence and 180-day all-cause mortality were not different. CONCLUSIONS: Vancomycin taper regimens did not provide benefit over vancomycin regimens without taper in preventing additional CDI recurrence in patients with first or second recurrent episodes in this propensity score-matched analysis.

Specific risk factors for Clostridium difficile-associated diarrhea: a prospective, multicenter, case control evaluation.

BACKGROUND: Clostridium difficile is a toxin-producing bacterium that is responsible for toxicity to the colonic mucosa, causing inflammation, necrosis, and, in some extreme cases, intestinal dilation and perforation. C difficile-associated diarrhea (CDAD) occurs when patients have a reduction in their natural gastrointestinal flora that allows for the proliferation of and toxin production by C difficile. METHODS: Using a multicenter, prospective observational case control study, we assessed and quantified risk factors associated with the development of diarrhea caused by Clostridium difficile, with particular attention to antibiotic use. All hospitalized patients with diarrhea requiring a C difficile toxin test as part of their routine clinical workup were considered for study inclusion. Patients with a negative specimen (controls) were considered for enrollment if matched (by age, sex, length of stay, and institution) to a case. Variables associated with CDAD were identified using univariate analysis. Significant factors were then entered into multivariate logistic regression analysis to identify independent factors. RESULTS: There were no significant differences in antibiotic use between cases and controls. Patient severity, classified by Horn's Index, was significantly different between cases and controls (P = .0022). No other significant variables were identified. CONCLUSION: The severity of illness of the cases was classified as more severe than the controls, but no significant differences in antibiotic use were identified between the groups. The negative C difficile toxin studies on the well-matched control patients indicate a different etiology of diarrhea (such as antibiotic-associated diarrhea), which may have developed in the presence of similar antibiotic use as the cases.

Trends in Susceptibility Rates and Extended-Spectrum ß-Lactamase Production of Klebsiella pneumoniae in Bloodstream Infections Across the United States Veterans Affairs Healthcare System.

Klebsiella pneumoniae is an important pathogen, increasingly notorious for its ability to become resistant to antimicrobial agents. This study sought to characterize trends in antimicrobial susceptibility rates for K. pneumoniae causing bacteremias across the United States (U.S.) Veterans Healthcare Administration (VHA) from 2007 through 2013 utilizing a national clinical database. K. pneumoniae grew in 9,235 blood cultures from 8,414 patients. Nationally, ampicillin-sulbactam, ceftazidime, cefepime, ertapenem, fluoroquinolones, and amikacin demonstrated statistically significant susceptibility rate increases against K. pneumoniae in the 2010-2013 period versus the 2007-2009 period. No antimicrobial agent had a statistically significant nationwide susceptibility rate decrease. Of the 126 antibiotic-organism pairs tested among 9 U.S. regions, 18 demonstrated statistically significant susceptibility rate increases while 6 demonstrated statistically significant susceptibility rate decreases. The East North Central (eight agents), Mid-Atlantic (five agents), and South Atlantic (four agents) regions demonstrated statistically significant susceptibility rate increases for multiple antimicrobial agents. Of the 70 antibiotic-organism pairs tested among 5 different medical center complexity levels, 11 antibiotics demonstrated statistically significant susceptibility rate increases and 1 demonstrated a statistically significant rate decrease. Extended-spectrum ß-lactamase production did not significantly change over the study period across an available nationwide representation of 31 facilities (10.6% in 2007-2009 vs. 9.21% in 2010-2013, p=0.17). The South Atlantic and Mid-Atlantic regions had the highest prevalence of extended-spectrum ß-lactamase production in the two periods, respectively. The recent trend of generally increasing susceptibility rates for K. pneumoniae bloodstream isolates in this nationwide U.S. VHA study contrasts from other U.S. health system reports demonstrating increasing trends of antimicrobial resistance.